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7,904,646,696,503,546,000 | %0 Journal Article %T Crocin prevents acute angiotensin II-induced hypertension in anesthetized rats %J Avicenna Journal of Phytomedicine %I Mashhad University of Medical Sciences %Z 2228-7930 %A Shafei, Mohammad Naser %A Faramarzi Plangar, Abdolali %A Anaeigoudari, Akbar %A Khajavi Rad, Abolfazl %D 2017 %\ 06/01/2017 %V 7 %N 4 %P 345-352 %! Crocin prevents acute angiotensin II-induced hypertension in anesthetized rats %K Crocin %K Hypertension %K Heart rate %K Mean arterial pressure %K Angiotensin II %R 10.22038/ajp.2017.17438.1672 %X Objective: Angiotensin II (Ang II), the main product of renin-angiotensin system (RAS) has a well-known role in cardiovascular regulation. Over-production of Ang II is one of the important underlying mechanisms of hypertension. In this study, the effect of crocin on cardiovascular responses in rats with acute hypertension induced by Ang II was evaluated. Materials and methods: Rats were divided into six groups (n = 6): 1) Control: rats that received saline, 2) Ang II: rats that received Ang II (300 ng/kg) infused in two min, 3) Losartan (Los) + Ang II : rats that received Los (10 mg/kg, i.v) before Ang II, and 4-6) Crocin (Cro) + Ang II groups: rats that received three doses of crocin (50, 100 and 200 mg/kg, slow i.v) 10 min before Ang II. Femoral artery and vein were cannulated for recording of cardiovascular parameters and injection of drugs, respectively. Systolic blood pressure (SBP), mean arterial blood pressure (MAP) and heart rate (HR) were continuously recorded by power lab system. After injection of reagents and extracts, maximum changes (∆) of MAP, SBP and HR were recorded and compared with control group. Results: Ang II (300 ng/kg) increased maximal changes in MAP, SBP and HR compared to control group (p<0.001) and Los significantly attenuated these effects of Ang II (p<0.001). Maximal changes of MAP, SBP and HR induced by Ang II, were significantly attenuated by pretreatment with all doses of crocin (50,100 and 200) (p Conclusion: Based on the effects of crocin on acute Ang II-induced hypertension, it is hypothesized that the cardiovascular improving effects of crocin may be mediated via suppressing of RAS. %U http://ajp.mums.ac.ir/article_8613_b52287f1c1733f55685e387dee6d333a.pdf | {
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-4,738,081,583,487,378,000 | bacterid
bacterid
[bak´ter-id]
a skin eruption due to bacterial infection elsewhere in the body.
bac·ter·id
(bak'ter-id),
1. A recurrent or persistent eruption of discrete sterile pustules of the palms and soles, thought to be an allergic response to bacterial infection at a remote site.
2. A dissemination of a previously localized bacterial skin infection.
[bacteria + -id (1)]
bacterid
(1) An “id” reaction attributed to bacteria elsewhere in the body.
(2) A bacterial dermatitis.
bac·ter·id
(bak'tĕr-id)
1. A recurrent or persistent eruption of discrete sterile pustules of the palms and soles, thought to be an allergic response to bacterial infection at a remote site.
2. A dissemination of a previously localized bacterial skin infection.
[bacteria + -id (1)]
bac·ter·id
(bak'tĕr-id)
1. A recurrent or persistent eruption of discrete sterile pustules of the palms and soles, thought to be an allergic response to bacterial infection at a remote site.
2. A dissemination of a previously localized bacterial skin infection.
[bacteria + -id (1)]
Mentioned in ?
References in periodicals archive ?
Unahco is the manufacturer and distributor of animal nutrition and healthcare products Pigrolac, Early Wean, Mamapro, Sarimanok, Vetracin, Jectran, Latigo, Bexan, Bacterid and Apralyte.
A similar reaction may be seen with distant bacterial infections and is termed "panniculitis bacterid." (24) The lesions typically occur on the lower extremities, and they preferentially affect the calves in erythema induratum.
Although the lesions are sterile, the histopathologic features of erythema induratum and panniculitic bacterid are very similar to those of infective panniculitis.
Acute infectious id panniculitis/ panniculitic bacterid: a distinctive form of neutrophilic lobular panniculitis.
B complex 3 bottles oxytetracycline la 100ml 10 can wound spray 80g 5 liter albendazole 15% oral suspension 10 vial enfloxacin bacterid 10ml 5 vial oxytocin 5ml 12 bottle vitamin b complex | {
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1,615,314,792,171,676,400 | Why does testicular atrophy occur in men?
.
Table of contents
• Why is this happening?
• How does the disease manifest itself?
• Elimination of atrophic phenomena
Atrophy of the testicles is a pathological process in which the external genital organs decrease. Violation, in turn, leads to malfunctions in the process of spermatogenesis, thereby negatively affecting the reproductive function in men.
In reality, testicular atrophy is rare, but nevertheless, there are a number of prerequisites for the occurrence of a similar problem in men of different ages. In addition, men retain the ability to intercourse, although the chances of conception are minimal.This leads to the fact that most patients refuse to visit a doctor or are unaware of the presence of pathology in themselves.
.
Why is this happening?
Atrophy of the testicle both left and right can occur due to various factors. There are various reasons. The first of these is the violation of normal testicle blood flow. This is due to vascular damage, resulting in a long ischemia of the tissues, which are not fully provided with oxygen and necessary substances.
The causes of the development of pathology can be covered in the transferred diseases. Especially it concerns those men who have suffered a trauma in the inguinal region or operation. In this case, testicular atrophy may appear after a long period of time, signs of tissue damage have long disappeared.
Among the diseases that provoke testicular atrophy in men, varicocele and hydrocele. In the first case, the disease is not a complication of varicocele, but is a pathology and develops against the background of existing problems with the vascular system. With hydrocele, surgeon intervention is necessary. In addition, atrophy of the testicle can be a consequence of an inflammatory disease that occurs in the groin. Inflammatory processes lead to a violation of nerve conduction, which, in turn, disturbs capillary blood flow.
.
Quite often, atrophy occurs in children and is a consequence of cryptorchidism. If there is no correct and timely treatment, there is a violation of blood circulation, there are various adverse factors.
The appearance of a problem can lead to a failure of the hormonal background. This occurs with severe obesity, and in violation of the regulation of sex hormones. Atrophy can appear and after the twisting of the spermatic cord, often the problem occurs in men who have had an infectious disease.
It should be noted that there is a difference between atrophy and hyperplasia. In the case of atrophy, the patient has a decrease in the size of a healthy organ, which after a while begins to die off. With hyperplasia, the testicle initially develops poorly or does not develop completely. As a result, it does not grow to the right size, and the patient loses its reproductive function.
How does the disease manifest itself?
Most often, negative changes in the testicles do not lead to the manifestation of the general symptoms of the disease. Some patients may experience weakness, decreased sexual desire, apathy. In men, there is often a change in the figure, which acquires feminine features. Nevertheless, there is an external change in the testicle, the symptoms of this are immediately apparent. This is clearly seen in both physical examination and palpation of both testicles. Sexual function in some cases is preserved, but the genitals look flabby, there is a further reduction in size.
To identify laboratory symptoms of the disorder, it is necessary to pass tests for the spermogram. This method will clearly show the presence of a problem, since atrophy leads to a reduction in the number of spermatozoa and sperm in general. Even the atrophy of one of the testicles is accompanied by a similar phenomenon.
It should be noted that there is a connection between both testicles, which is represented by a neuro-humoral regulation. Therefore, when there are any changes in one testicle, one should expect the appearance of similar signs in the other.
The patient is observed a change in the psyche, characterized by its frustration. For men, the sexual function is extremely important, because it makes them men. Any failure in its work in any case leads to a depressed state, so the patient needs the help of a psychologist.
Elimination of atrophic phenomena
When setting such a diagnosis, there can be no question of any treatment.
.
To cure a sick egg is impossible, therefore it is removed, as it leads to changes in a healthy testicle, as was mentioned earlier.
In this regard, you can use only preventive measures aimed at preventing the development of pathology.
To avoid such phenomena, it is necessary to treat diseases that can cause atrophy. It is necessary timely and correct treatment for torsion, genital injuries, correct treatment of infectious diseases.
At the moment there are no effective methods of treatment. Nevertheless, etiotropic therapy may have a somewhat positive effect, but only if the factor, such as the presence of a provoking factor, has been taken into account. If a man has a problem with the vascular system, he is prescribed pentoxifylline, trental and actovegin. Admission of these drugs leads to improved blood supply, helps to provide tissues with the necessary amount of oxygen and nutrients.
With the goal of normalizing the neuroregulatory function, galantamine is used. In Russia, the most accessible means of this group is Nivalin. Before using it, you should consult with your doctor and use cautiously, since the use of this medicine may lead to an allergic reaction.
x
http://youtu.be/ZyRIe9aie1Q
It should be remembered that it is necessary to monitor the patient and his condition, especially when carrying out hormonal therapy. If signs of atrophy appear further, then further use of medications should be ruled out. Only in those situations where the benefits of the steroid used are greater than the harm, it is possible to use such drugs to treat the disease.
Thus, the description of atrophy involves changing the appearance of the organs, the appearance of painful sensations and, in some cases, general weakness. The first need is to consult a specialist who determines the further treatment of the patient.
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93,657,529,291,827,360 | How Do I Know Someone Is Experiencing Anxiety or Depression?
— Written By
en Español
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If you or someone you care about feels overwhelmed with emotions like sadness, depression or anxiety, or like you want to harm yourself or others call 911.
You can also contact the Substance Abuse and Mental Health Services Administration’s (SAMHSA) Disaster Distress Helpline at 800-985-5990, the National Suicide Prevention Lifeline at 800-273-8255 or text MHFA to 741741 to talk to a Crisis Text Line counselor.
We know that these days of COVID-19 are difficult and can bring feelings of anxiety or depression. Practicing physical distancing from your loved ones, hearing constantly changing news on every channel, and not knowing what will happen is scary.
That’s why it is important that you use information from the Mental Health First Aid curriculum to not only take care of your own mental health, but also support those around you who might be experiencing anxiety or depression.
When people describe their anxiety, they may use terms such as anxious, stressed, freaking out, panicky, wound upnervouson edgeworriedtenseoverwhelmed or hassled.
Anxiety can vary in severity from mild uneasiness to a terrifying panic attack. Anxiety can also vary in how long it lasts — from a few moments to many years.
Although everyday anxiety is an unpleasant state, it can be quite useful in helping a person avoid dangerous situations and motivating them to solve everyday problems. An anxiety disorder differs from everyday anxiety in the following ways:
1. It is more severe.
2. It is persistent.
3. It interferes with the person’s activities, studies, and family and social relationships.
4. If not treated, it continues to cause real pain and distress, and it can lead to poor academic performance, impaired social functioning and other negative outcomes.
Depression causes feelings of sadness and/or a loss of interest in activities once enjoyed. It can lead to a variety of physical and emotional problems, such as irritability. A person’s pain may be invisible to you while it is still interfering with functioning.
If you or someone you know is experiencing intense worry or sadness about current or future events, and it is disrupting their ability to cope with everyday life, there is support available.
There are self-help strategies and treatments that can be effective with anxiety or depression. There are also behavioral health care providers who can provide services by phone and/or secure videoconferencing, so they will be able to maintain physical distancing. If you don’t know where to start, reach out to your primary care physician.
Thank you for choosing to #BeTheDifference with Mental Health First Aid. Together, we can get through this difficult time and support our loved ones along the way.
By Rubina Kapil on March 20, 2020
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6,060,005,563,947,914,000 | Does A Pedal Exerciser Help Lose Weight?
If you’re on a mission to shed some extra pounds, you’ve probably wondered, “Does a pedal exerciser help lose weight?” Well, you’re in luck because I’ve got all the juicy details for you. Pedal exercisers, those nifty little devices designed to simulate cycling, have been gaining popularity as a convenient and accessible way to get your heart rate up and burn calories. But do they really make a significant impact on your weight loss journey? Let’s dig in and find out!
When it comes to losing weight, finding an exercise routine that fits seamlessly into your lifestyle is key. That’s where pedal exercisers come into play. These compact machines can be used while you’re sitting at your desk, watching TV, or even reading a book. They offer a low-impact cardiovascular workout that gets your blood flowing and your muscles working. Plus, they’re perfect for those who may have mobility issues or joint pain, as they provide a gentle and safe way to get moving. But does all this pedaling actually translate into weight loss? Well, my friend, let’s explore the science behind it and uncover the truth together.
Does a Pedal Exerciser Help Lose Weight?
Does a Pedal Exerciser Help Lose Weight?
When it comes to weight loss, finding an exercise routine that fits into your lifestyle and preferences is crucial. One option that many people consider is using a pedal exerciser. These compact devices allow you to pedal away while sitting down, making them convenient for use at home or in the office. But do pedal exercisers actually help with weight loss? Let’s take a closer look.
The Science Behind Pedal Exercisers
Pedal exercisers, also known as mini exercise bikes or under-desk bikes, provide a low-impact cardiovascular workout. By pedaling, you engage your leg muscles and increase your heart rate, which can help burn calories. However, it’s important to note that the number of calories burned during a pedal exercise session may be lower compared to other forms of aerobic exercise, such as running or cycling outdoors.
Additionally, the intensity of your workout plays a role in weight loss. Pedal exercisers typically offer adjustable resistance levels, allowing you to customize the difficulty of your workout. By increasing the resistance, you can challenge your muscles and elevate your heart rate, resulting in a more effective calorie burn.
The Benefits of Pedal Exercisers
While pedal exercisers may not provide the same calorie burn as higher-intensity workouts, they offer several benefits that make them a viable option for weight loss:
1. Convenience: Pedal exercisers are compact and portable, making them easy to use at home or even at work. You can pedal while watching TV, reading a book, or working at your desk, allowing you to incorporate exercise into your daily routine without sacrificing time.
2. Low-Impact: Unlike activities like running or jumping, pedal exercises are gentle on your joints. This makes them suitable for individuals with joint pain, arthritis, or other conditions that may limit high-impact exercise.
3. Multi-Tasking: Pedal exercisers provide an opportunity to engage in light physical activity while performing other tasks. This can be especially beneficial for those with a sedentary lifestyle or individuals who struggle to find time for dedicated exercise.
Maximizing Weight Loss with a Pedal Exerciser
If you’re looking to lose weight with a pedal exerciser, there are a few strategies you can implement:
1. Vary Your Intensity: To increase your calorie burn, alternate between periods of higher resistance and lower resistance during your workout. This variation challenges your muscles and keeps your body guessing, leading to more effective weight loss.
2. Combine with Strength Training: While pedal exercisers primarily focus on cardiovascular exercise, incorporating strength training exercises such as squats or lunges can help build muscle and boost your metabolism. This can contribute to greater weight loss over time.
3. Monitor Your Progress: Keep track of your exercise sessions and gradually increase the duration and intensity of your workouts. This progressive overload can help prevent plateaus and ensure consistent weight loss results.
Conclusion
While pedal exercisers may not provide the same calorie burn as high-intensity workouts, they can still be a valuable tool for weight loss. Their convenience, low-impact nature, and ability to incorporate exercise into daily activities make them an attractive option for those looking to shed pounds. Remember, consistency and a balanced approach to exercise and nutrition are key to achieving and maintaining weight loss goals. So, if you’re considering a pedal exerciser, give it a try and see if it fits into your fitness routine.
Key Takeaways: Does a Pedal Exerciser Help Lose Weight?
• A pedal exerciser can be a helpful tool for weight loss.
• Using a pedal exerciser regularly can increase calorie burn and aid in weight management.
• It provides a convenient and low-impact way to engage in physical activity.
• Pairing pedal exercises with a healthy diet can enhance weight loss results.
• Consistency is key – regular use of a pedal exerciser is important for seeing weight loss benefits.
Frequently Asked Questions
1. How does a pedal exerciser help with weight loss?
A pedal exerciser is a compact and portable exercise machine that allows you to pedal while seated. It provides a low-impact cardiovascular workout that can help burn calories and contribute to weight loss. When you pedal on a pedal exerciser, your leg muscles are engaged, which increases your heart rate and boosts your metabolism. This increased activity helps to burn calories and fat, ultimately aiding in weight loss.
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In addition to burning calories, a pedal exerciser can also help tone and strengthen your leg muscles. Regular use of a pedal exerciser can lead to improved muscle definition and increased muscle mass, which can contribute to a higher metabolic rate. This means that even when you’re not using the pedal exerciser, your body will continue to burn more calories, making weight loss more achievable.
2. Is a pedal exerciser an effective way to lose weight?
While a pedal exerciser can be a helpful tool in your weight loss journey, it is important to remember that it should be used in conjunction with a balanced diet and other forms of exercise for optimal results. While pedaling on a pedal exerciser can burn calories, it may not provide the same intensity and calorie burn as more vigorous forms of exercise like running or cycling.
However, a pedal exerciser can be a great option for individuals who may have physical limitations or prefer a low-impact exercise. It can be used as a convenient way to incorporate physical activity into your daily routine, helping you to burn extra calories and contribute to weight loss over time.
3. How often should I use a pedal exerciser to lose weight?
The frequency of using a pedal exerciser for weight loss will depend on your individual fitness goals and abilities. It is generally recommended to aim for at least 150 minutes of moderate-intensity aerobic activity per week for weight loss. This can be divided into smaller sessions throughout the week.
You can start by using a pedal exerciser for 10-15 minutes at a time and gradually increase the duration as you build stamina. Aim to use the pedal exerciser at least 3-5 times a week to see noticeable results in terms of weight loss. Remember to listen to your body and consult with a healthcare professional before starting any new exercise routine.
4. Can a pedal exerciser help with overall fitness?
Yes, a pedal exerciser can contribute to overall fitness. While it primarily targets the muscles in your legs, regular use of a pedal exerciser can also improve cardiovascular health, increase endurance, and enhance muscle tone. It provides a convenient way to incorporate physical activity into your daily routine, even if you have limited mobility or access to a gym.
In addition, using a pedal exerciser can help improve joint flexibility and range of motion. It is a low-impact exercise that puts minimal stress on your joints, making it suitable for individuals with arthritis or joint pain. By incorporating a pedal exerciser into your fitness routine, you can improve your overall fitness level and enhance your overall well-being.
5. Are there any other benefits of using a pedal exerciser besides weight loss?
Absolutely! While weight loss is one of the potential benefits of using a pedal exerciser, there are many other advantages to incorporating this exercise machine into your daily routine. Regular use of a pedal exerciser can help improve cardiovascular health, increase energy levels, reduce stress, and improve mental clarity.
Furthermore, using a pedal exerciser can be a great way to engage in physical activity while multitasking. You can pedal while watching TV, reading a book, or working at your desk. It provides a convenient and time-efficient way to stay active throughout the day. Additionally, a pedal exerciser is a cost-effective alternative to larger exercise machines and can be easily stored in small spaces.
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Final Summary: Can a Pedal Exerciser Help You Lose Weight?
So, we’ve reached the end of our journey exploring the question: “Does a pedal exerciser help lose weight?” And the answer is a resounding yes! Using a pedal exerciser can be a fantastic way to get your heart pumping, burn calories, and ultimately shed those extra pounds. But remember, like any exercise equipment, it’s not a magical solution that will instantly transform your body. It’s a tool that, when used consistently and in conjunction with a healthy diet, can contribute to your weight loss journey.
In conclusion, a pedal exerciser offers a convenient and accessible way to incorporate exercise into your daily routine. It allows you to engage in physical activity regardless of the weather or time constraints. Plus, it’s gentle on your joints, making it suitable for individuals with mobility issues or those recovering from injuries. Whether you use it while watching TV, working at your desk, or even reading a book, a pedal exerciser can help you burn calories, improve cardiovascular fitness, and ultimately support your weight loss goals.
So, if you’re looking for an effective and convenient way to lose weight, consider incorporating a pedal exerciser into your fitness routine. Remember, consistency is key, so make it a habit to pedal away regularly. Combine it with a balanced diet, and you’re well on your way to achieving your weight loss goals. Get ready to feel the burn and watch those
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188,183,461,034,395,400 | 伝えたい！ 歯の疑問：矯正歯科
歯周病でも歯列矯正は出来るのか？
皆様の健康をトータルサポート。
矯正装置を外したら歯周病が悪化するという事はありません。むしろ矯正装置は適切なブラッシングを阻害します。歯周病で歯列矯正をしていても、顎の骨が折れやすくなることはありません。
歯周病と矯正歯科との関連
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• 友だち追加
歯並びが悪く乱杭歯で歯周病になっているケースを矯正治療で治す
初期の歯周病でプラークコントロールが不良です。乱杭歯なので、歯列矯正が必要なケースです。
質問に対する回答
Q1
矯正装置を外してから歯周病が悪化したのですが。
こんにちは。33歳女性です。 矯正装置をはずした２年ほど前から、急激に歯周病が悪化したような気がします。
１ヶ月に１度、歯茎全体が痛くなり炎症を起こしているのか、指で少し押さえただけでも真っ赤になるほど歯茎から血が出ます。ゴールデンウィークに診察して頂いたのですが、歯周ポケットは総て3ミリ（１箇所は4ミリ）でした。骨の吸収に関しては何も言われませんでした。ブラッシング指導の通り歯磨きしているのですが・・
歯周病を専門に掲げてる医院のほうがいいのかしら。 体調が悪くなると弱いところに出るといいますが、そういう類のものなのでしょうか（一過性？）それとも確実に歯周病が進行しているということなのでしょうか？それを食い止めるにはどうしたら…。
あと、外科手術を併用した矯正方法（上下あごとも）だったのですが、それも何か影響しているのでしょうか。 お忙しいところ恐れ入りますが、ご回答お待ちしています。
A
歯列矯正を行って歯並びが良くなったのですから歯磨きもきちんと出来るようになっているはずです。ですから矯正装置を外した事と歯周病になっている事は全く因果関係はないと言ってよいでしょう。
歯周ポケットという視点から言えば、３ｍｍ程度ですので歯周病ではなく正常の範囲ということもできます。 しかし、歯肉からの出血がありますので、あきらかに歯周病になっています。歯槽骨の吸収がないのであれば、 歯周病の初期状態、つまり歯肉炎ということになります。
歯肉炎の程度でしたら、的確なブラッシングで治癒することがほとんどです。歯肉炎の状態が続いているようですから十分なプラークコントロールが出来ていないのではないでしょうか。
自宅で染め出し液を使って磨き残しのチェックを行ってみると良いでしょう。また、ポイックウォーターを使って歯磨きをするもの効果があるでしょう。
ただ、歯石が付着している場合には歯科医院で取ってもらわなくてはなりません。歯石は１度とってもまたついてしまうものです。 個人差がありますが、早い人で３か月もするともう付いている人もいます。
また、ブラッシングだけでは的確に口腔内を綺麗にする事が出来ない人もかなりいるようです。そこで、歯科医院においてPMTCを定期的（３か月に一度）受けることを お勧めします。PMTCやエアーフローを定期的に受けることで、歯石の付着もかなり防ぐことが出来ます。また、PMTCやエアーフローでは歯周ポケット内の細菌量のコントロールが出来ますから非常に重要な処置と思います。
外科手術を併用した矯正治療と歯周病との因果関係はないと思います。
歯科医院の選択
1. 歯科衛生士を雇用していて、歯ブラシのやり方の指導をしっかり行っている。
2. PMTCを行っている。
3. 定期的にメインテナンス（歯石取り、PMTC）を行っている。
以上をしっかり実施している歯科医院であることが望ましいです。
Q2
歯周病ですが歯列矯正中です。あごの骨は折れやすくなりますか？
歯周病も手遅れと言われました。骨が溶けていると。現在歯列矯正中です。顔色はあごの付近が赤黒く、小鼻の横が赤くなっています。 夜、生ごみのにおいを感じ、鼻が押されるような感じです。
あごの骨は折れやすくなりますか？ そのような時は何処に診てもらうのでしょうか？
A
現在、歯列矯正中ということですので、歯に力がかかっていますから、鼻が押されるような感覚が起こっているのかもしれません。
矯正治療には、骨が折れるということありませんのでご心配はいりません。また、過去にそのような症例があったという報告は、一切ありません。
歯周病であっても重度歯周病でなければ、あるいは歯周病がある程度コントロールされていれば、矯正治療を行っても差し支えないと思います。
生ごみの臭いを感じるということについては、口腔内に何らかの問題があるのかもしれません。歯周病が進行しているということですから、歯周病菌による臭いなのかもしれません。または、口臭は自臭症と他臭症とに分類されますが、全く臭いの原因がなく、においだけを感じる自臭症なのかもしれません。直接診断していないので、明確な回答が出来ないのが残念です。
いずれにしても、歯科医師に症状を明確に話して診断を仰いでください。
スポンサーリンク
歯列矯正のご相談は
ふかさわ歯科クリニック院長 歯科医師の深沢一
執筆者 院長 深沢一
日本矯正歯科学会認定医の堀内洋輔が担当
お気軽にご相談下さい。
相談・カウンセリング受付中
電話：03-3676-1058
東京都江戸川区、千葉県から来院多数、
都営新宿線篠崎駅から徒歩1分のふかさわ歯科クリニック
診療時間
月〜金曜日 土曜日 日曜日
9:00〜19:30 8:00〜18:00 8:00〜17:30
歯列矯正関連コンテンツ
顎関節症で正中を顔の中心ラインに矯正で合わせる必要があるか？
顎関節症で正中を顔の中心ラインに矯正で合わせる必要があるか？
歯が痛くなる原因と自宅ですぐに出来る応急処置法について解説。冷たいもの・熱いものを食べた時の痛み、噛んだ時の痛み、歯茎の腫れなど、様々な視点から自分の痛みがどこから来ているのか判断出来るように…
矯正治療後の歯肉退縮によるブラックトライアングルは治るのか？
矯正治療後の歯肉退縮によるブラックトライアングルは治るのか？
歯肉退縮は歯周病や矯正治療の後に起こったり、歯ぎしりや食いしばりなど強い力が歯にかかり続けると起こります。歯茎が下がると前歯に三角形の黒い隙間、ブラックトライアングルができます。ブラックトライアングルの治療にはヒアルロン酸注入が効果的です…
カテゴリ
ふかさわ歯科
クリニックのご案内
患者様の
「こうしてほしい」を実現します。
ふかさわ歯科クリニックでは、納得いくまでのカウンセリング、安心してお子様を預けられるキッズスペースと保育士、
可能な限り痛くない無痛治療、拡大鏡・セファロ・血液の遠心分離機・拡大鏡・レーザー・ポイックウォーター・画像解析システムなどの
最新機器を利用した総合治療を実施しております。
また、診療室は個室・半個室・防音個室があり、ベビーカーや車いすでも入って頂けるスペースを確保しています。
地域に密着した歯科医院をこれからも目指して行きます。
診療についてのご相談
お電話またはフォームにてご連絡ください。
03−3676−1058
オンライン予約
診療時間
9:00～13:00 ×
14:30～19:30 ×
8:00～13:00
14:00～18:00
14:00～17:30
※祝祭日も同様です。概ね最終受付時間は、診療終了時間の30分前です。
ブログを見る | {
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-8,555,403,438,613,887,000 |
during chest radiography the act of inspiration depresses the abdominal viscera
during chest radiography the act of inspiration:
• 1- elevates the diaphragm
• 2- raises the ribs
• 3- depresses the abdominal viscera
• a. 1 only
• b.1 and 2 only
• c.2and 3 only
• d . 1,2 and 3
elevate the abdominal viscera:
That's not correct. During chest radiography, the act of inspiration elevates the abdominal viscera. This is because when the diaphragm contracts during inspiration, it moves downward, which pushes the abdominal viscera down and away from the heart and lungs. This allows for better visualization of the heart and lungs on the chest X-ray.
Diaphragm contraction:
When a patient takes a deep breath in during chest radiography, the diaphragm contracts and moves downward. This pushes the abdominal viscera down and away from the heart and lungs, which makes it easier to see the heart and lungs on the X-ray.
If the patient does not take a deep breath in, the diaphragm will not be fully contracted and the abdominal viscera will not be pushed down as far. This can make it more difficult to see the heart and lungs on the X-ray.
Chest X-ray:
In some cases, the patient may be asked to lie on their side or stomach for the chest X-ray. This can help to move the abdominal viscera away from the heart and lungs, which can also make it easier to see the heart and lungs on the X-ray.
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-4,202,901,845,538,120,000 | Skip to main content
Table 2 Intraclass and bivariate correlation coefficients comparing estimated intakes by weighed food records and 24-h dietary recallsa
From: Validation of triple pass 24-hour dietary recall in Ugandan children by simultaneous weighed food assessment
Nutrient Weighed Food Record Combined Dietary Recalls
Mean SD Mean SD ICC (95 % CI) r (p-value)
Energy (kJ) 6563 1706 6335 1537 0.98 (0.90–0.98) 0.96*
Protein (g) 40.0* 12.9 36.4* 11.4 0.97 (0.90–0.99) 0.985*
Iron (mg) 6.6 2.6 6.0 2.0 0.94 (0.84–0.98) 0.91*
1. SD standard deviation, ICC intraclass correlation coefficient, CI confidence interval, r correlation coefficient
2. aICCs compared absolute agreement of average measures, using a two-way random model
3. *p < 0.001
4. *p = 0.02 | {
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-8,992,650,931,859,338,000 | hydrogen peroxide vs alcohol as disinfectant
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Comparison of EPA Registered Hospital Disinfectants/Ready ...- hydrogen peroxide vs alcohol as disinfectant ,Peroxide 1.4% Hydrogen peroxide 55.0% Alcohol 0.5% Quat 14.85% Alcohol 0.25% Quat 0.28% Quat Signal Word (Toxicity Concern) CAUTION CAUTION CAUTION WARNING CAUTION CAUTION WARNING CAUTION CAUTION Required Surface Contact Time 1 min. 2 min. 3 min. 3 min. 10 min. 5 min. 2 min. 3 min. 3 min. “One Step” Disinfection On A Visibly …Chemical Disinfectants | Disinfection & Sterilization ...Dec 04, 2021·About Vs Alcohol Peroxide Rubbing Hydrogen . Hydrogen peroxide is a chemical which you can basically just find at home. hydrogen peroxide (0. Hydrogen peroxide has a finite shelf-life because, over time, it naturally decomposes into water and oxygen gas.
Hydrogen Peroxide or Rubbing Alcohol On A Wound? Neither ...
Oct 08, 2019·"The answer is you don't use hydrogen peroxide or alcohol," Dr. Ian says. "Now, our grandparents and parents used to do that, and the reason why they did that was because it actually kills the bacteria. The problem is, it's also killing the healthy cells around the wound — and that delays the healing."
Comparison of the efficacy of a hydrogen peroxide ... - PubMed
Objective: To compare a hydrogen peroxide dry-mist system and a 0.5% hypochlorite solution with respect to their ability to disinfect Clostridium difficile-contaminated surfaces in vitro and in situ. Design: Prospective, randomized, before-after trial. Setting: Two French hospitals affected by C. difficile. Intervention: In situ efficacy of disinfectants was assessed in rooms that had …
Table 1 | Disinfection & Sterilization Guidelines ...
Hydrogen peroxide (7.35%) and 0.23% peracetic acidacid; hydrogen peroxide 1% and peracetic acid 0.08% (will corrode metal instruments) n/a: n/a: Hydrogen peroxide 7.5% (will corrode copper, zinc, and brass) 6 h: Wet pasteurization at 70°C for 30 minutes with detergent cleaning 6: n/a: n/a
Hydrogen Peroxide or Rubbing Alcohol On A Wound? Neither ...
Oct 08, 2019·"The answer is you don't use hydrogen peroxide or alcohol," Dr. Ian says. "Now, our grandparents and parents used to do that, and the reason why they did that was because it actually kills the bacteria. The problem is, it's also killing the healthy cells around the wound — and that delays the healing."
Listerine Vs Hydrogen Peroxide - Bad Breath Stinks
Oct 02, 2018·Listerine Vs Hydrogen Peroxide. Products are everywhere that can help bad breath and other oral health issues. Listerine has been around for a long time, and is a product that is a common household name. Hydrogen Peroxide, on the other hand, isn’t as well-known as a mouthwash, but it is known for its powerful cleansing properties.
Efficacy of various disinfectants on microbially ...
The cost of each disinfectant for usage was estimated. Hexidine, 3.0% hydrogen peroxide and Listerine cost around ’ 6.80/-, ’ 1.80/- and ’ 9.40/-, when used as 20 ml once in 3 days, and the total cost per month is ’ 68/-, ’ 18/- and ’ 94/-, respectively. Among these disinfectants, the most economical is 3.0% hydrogen peroxide, which ...
Hydrogen Peroxide vs Bleach: How They Compare
Sep 02, 2019·Hydrogen peroxide is a popular antiseptic and cleansing agent with a multitude of uses. It is used in various industries because of its bleaching properties but it’s also used as a sterilizing agent and as a disinfectant. Hydrogen Peroxide is chemically known as H 2 0 2, a formula which may remind you of water (H 2 0).
Is alcohol just as effective for disinfecting ... - Quora
Answer (1 of 4): Alcohol (both ethanol and rubbing alcohol or isopropanol) and hydrogen peroxide use two different ways to kill living things. Alcohol can dissolve fats, including the lipids that make up the cell membrane, and it can pull water out …
How we know disinfectants should kill the COVID-19 coronavirus
Mar 13, 2020·Alcohol, Hydrogen peroxide (3%-NO higher), bleach (unexpired and properly diluted -as Charles describes) and Quaternary Ammonium are each effective at killing viruses. Please note that Vinegar ...
How to Use Hydrogen Peroxide Disinfectant (0.5% vs 3% vs ...
Nov 12, 2021·How to Use It the Right Way. Hydrogen peroxide is a staple cleaning agent and the active ingredient in many household cleaning solutions.. It is nice to use because you do not need to dilute it yourself. It comes diluted with purified water or with other inactive ingredients to a variety of concentration levels.. The hydrogen peroxide (H 2 O 2) (paid link) is typically …
5 Alternatives to Disinfecting with Alcohol
Jun 29, 2021·Hydrogen Peroxide You probably think about minor cuts and wounds when you hear hydrogen peroxide because this product is the go-to antiseptic for many decades. Although hydrogen peroxide is no longer recommended by doctors today for such uses, it remains a valuable household chemical because of its disinfectant, antiviral, and anti-bacterial ...
Quick Answer: Which Is Better Alcohol Or Hydrogen Peroxide ...
Disinfect your toothbrush Hydrogen peroxide is an effective disinfectant that can destroy essential components of germ cells and deactivate a wide range of microorganisms. Antiseptic mouthwash contains various active ingredients, such as alcohol, menthol, and eucalyptol, which can all kill bacteria.
Hydrogen Peroxide vs Rubbing Alcohol ... - Health Guide …
Mar 09, 2021·For instance, hydrogen peroxide is an oxidizer that may damage the tissue and capillaries, whereas rubbing alcohol will also damage tissue and cause burns. As for what you should do when cleaning cuts and wounds, most healthcare professionals will point out simply using normal saline solution. A normal saline solution contains 0.9% sodium chloride.
Iodine vs. Hydrogen Peroxide vs. Alcohol? : answers - reddit
Hydrogen peroxide is quite a potent disinfectant, however, it is also an unstable compound which will eventually give off oxygen and turn into ordinary water. Iodine, in comparison, is completely stable. The alcohol can evaporate, but even if that happens you can just add more. As a result, I prefer iodine as a disinfectant.
Hydrogen Peroxide vs. Bleach: Which is the Better ...
Add 2 ounces of hydrogen peroxide to the detergent compartment of your dishwasher and run it along with your regular detergent (this will help disinfect your dishes). Pour it over your toothbrush for a quick disinfectant (then rinse with water). Add it to your humidifier and run it as usual to clean the system’s interior. Use one pint of ...
Comparison of the efficacy of a hydrogen peroxide ... - PubMed
Objective: To compare a hydrogen peroxide dry-mist system and a 0.5% hypochlorite solution with respect to their ability to disinfect Clostridium difficile-contaminated surfaces in vitro and in situ. Design: Prospective, randomized, before-after trial. Setting: Two French hospitals affected by C. difficile. Intervention: In situ efficacy of disinfectants was assessed in rooms that had …
Hydrogen peroxide vs Isopropyl alcohol: What to use for ...
Mar 12, 2020·Hydrogen peroxide vs Isopropyl alcohol: What to use for disinfection? We hate to say it, but it depends. Isopropyl alcohol is more effective against lipid viruses i ncluding hepatitis B and C, HIV, influenza, and respiratory syncytial virus, whereas hydrogen peroxide – against non-enveloped viruses, like rotavirus, coxsackieviruses, or poliovirus.
Why You Should Stop Using Hydrogen Peroxide on Wounds by ...
May 30, 2018·Hydrogen peroxide is a chemical compound with the formula H2O2 and has been used as a first aid antiseptic for injured skin since the 1920’s. The simplest peroxide, it is used as an antiseptic agent, bleaching agent and an oxidizer. It is a common ‘go to’ when there is a wound, and it can usually be found in most household’s first aid kits.
Rubbing Alcohol vs. Hydrogen Peroxide - WebMD
Rubbing alcohol can kill them within 10 seconds. Hydrogen peroxide is another antiseptic, or disinfectant, that kills viruses and various forms of bacteria. …
Question: What Happens If You Mix Rubbing Alcohol And ...
When do you use hydrogen peroxide vs rubbing alcohol? In basic, rubbing alcohol is better at killing germs for your arms, because it’s gentler for your pores and skin than hydrogen peroxide. Hydrogen peroxide is best when it’s allowed to take a seat on surfaces for no less than 10 mins at room temperature.
Comparing Different Disinfectants – Stanford Environmental ...
Consult manufacturer directions to determine the efficacy of the disinfectant against the biohazards in your lab and be sure to allow for sufficient contact time. Some disinfectants appropriate for lab use include: household bleach (5-10% solution), quaternary ammonium compounds, and phenolic compounds.
At a glance: Disinfectant Tables - Public Health Ontario
Limited use as disinfectant because of narrow microbiocidal spectrum; not recommended as an antiseptic 3% hydrogen peroxide 10 minutes Inexpensive; f ast - acting; environmentally friendly Oxidizing properties may be destructive to some equipment (brass, zinc, copper and nickel/silver) 0.5% hydrogen peroxide (enhanced action formulation)
Table 1 | Disinfection & Sterilization Guidelines ...
Hydrogen peroxide (7.35%) and 0.23% peracetic acidacid; hydrogen peroxide 1% and peracetic acid 0.08% (will corrode metal instruments) n/a: n/a: Hydrogen peroxide 7.5% (will corrode copper, zinc, and brass) 6 h: Wet pasteurization at 70°C for 30 minutes with detergent cleaning 6: n/a: n/a
Hydrogen Peroxide vs Rubbing Alcohol ... - Health Guide Net
Mar 09, 2021·Hydrogen Peroxide vs Rubbing Alcohol For Cuts & Wounds – Differences and Side Effects A wound is a break in the skin surface, resulting in a potential bacterial contamination. Nearly everyone will experience an open wound at some point during their life.
Listerine Vs Hydrogen Peroxide - Bad Breath Stinks
Oct 02, 2018·Listerine Vs Hydrogen Peroxide. Products are everywhere that can help bad breath and other oral health issues. Listerine has been around for a long time, and is a product that is a common household name. Hydrogen Peroxide, on the other hand, isn’t as well-known as a mouthwash, but it is known for its powerful cleansing properties.
Hydrogen Rubbing Vs Alcohol Peroxide [DFGT5H]
Dec 04, 2021·About Vs Alcohol Peroxide Rubbing Hydrogen . Hydrogen peroxide is a chemical which you can basically just find at home. hydrogen peroxide (0. Hydrogen peroxide has a finite shelf-life because, over time, it naturally decomposes into water and oxygen gas. | {
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Biology LibreTexts
14.3: Divisions of the Skeletal System
• Page ID
22546
• Skulls on Display
This somewhat macabre display can be viewed at the Slovak National Museum in Bratislava, Slovakia. The skulls are meant to represent normal human skeletal anatomy. The skull is part of the axial skeleton, which is one of the two major divisions of the human skeleton. The other division is the appendicular skeleton.
Human skulls on display
Figure \(\PageIndex{1}\): Image used with permission (CCO; Kiwiev via wikimedia.org).
Axial Skeleton
The axial skeleton, shown in blue in Figure \(\PageIndex{2}\), consists of a total of 80 bones. Besides the skull, it includes the rib cage and vertebral column. It also includes the three tiny ossicles (hammer, anvil, and stirrup) in the middle ear and the hyoid bone in the throat, to which the tongue and some other soft tissues are attached.
Axial skeleton diagram
Figure \(\PageIndex{2}\): The bones of the axial skeleton are shown here in blue. Image used with permission (public domain; LadyofHats Mariana Ruiz Villarreal via wikimedia.org).
Skull
The skull is the part of the human skeleton that provides a bony framework for the head. It consists of 22 different bones. There are 8 bones in the cranium, which encloses the brain, and 14 bones in the face.
Cranium
The cranium, sometimes called the braincase, forms the entire upper portion of the skull. As shown in the figure below, it consists of eight bones: one frontal bone, two parietal bones, two temporal bones, one occipital bone, one sphenoid bone, and one ethmoid bone. The ethmoid bone separates the nasal cavity from the brain. The sphenoid bone is one of several bones, including the frontal bone, that helps form the eye sockets. The other bones of the cranium are large and plate-like. They cover and protect the brain. The bottom of the skull has openings for major blood vessels and nerves. A large opening, called the foramen magnum, allows the spinal cord and brain to connect.
Cranial bones
Figure \(\PageIndex{3}\): The cranium consists of eight bones that are fused together at their joints. Image used with permission (CCO; Edoarado; via wikimedia.org)
Facial Bones
The 14 facial bones of the skull are located below the frontal bone of the cranium. They are depicted in the figure below. Large bones in the face include the upper jaw bones, or maxillae (singular, maxilla), which form the middle part of the face and the bottom of the two eye sockets. The maxillae are fused together except for an opening between them for the nose. The lower edge of the maxillae contains sockets for the upper teeth. The lower jaw bone, or mandible, is also large. The top edge of the mandible contains sockets for the lower teeth. The mandible opens and closes to chew food and is controlled by strong muscles. There are two zygomatic or cheekbones and two nasal bones. The nasal region also contains seven smaller bones, as indicated in the figure.
Facial bones
Figure \(\PageIndex{4}\): The 14 bones that make up the face are labeled in this drawing of the skull. (public domain; Was a bee via wikimedia.org).
Vertebral Column
The vertebral column, also called the spine or backbone, is the flexible column of vertebrae (singular, vertebra) that connects the trunk with the skull and encloses the spinal cord. It consists of 33 vertebrae that are divided into five regions, as shown in Figure \(\PageIndex{5}\): the cervical, thoracic, lumbar, sacral, and coccygeal regions. From the neck down, the first 24 vertebrae (cervical, thoracic, and lumbar) are individual bones. The five sacral vertebrae are fused together, as are the four coccygeal vertebrae.
Vertebral Column
Figure \(\PageIndex{5}\): The vertebral column consists of 24 individual vertebrae that are separated by intervertebral discs of cartilage. An additional 9 vertebrae are fused together at the base of the spine. Note the S-shaped curve of the vertebral column in the profile view on the right. (CC BY 3.0; OpenStax College; via wikimedia.org)
The human vertebral column reflects adaptations for upright bipedal locomotion. For example, the vertebral column is less like a rigid column than an S-shaped spring (see a profile view in the figure above). Although newborn infants have a relatively straight spine, the curves develop as the backbone starts taking on its support functions, such as keeping the trunk erect, holding up the head, and helping to anchor the limbs. The S shape of the vertebral column allows it to act as a shock absorber, absorbing much of the jarring of walking and running so the forces are not transmitted directly from the pelvis to the skull. The S shape also helps protect the spine from breaking, which would be more likely with a straight, more rigid vertebral column. In addition, the S shape helps to distribute the weight of the body, and particularly of the internal organs, so the weight load is not all at the bottom, as would occur with a straight spine.
Rib Cage
The rib cage (also called thoracic cage) is aptly named because it forms a sort of cage that holds within it the organs of the upper part of the trunk, including the heart and lungs (Figure \(\PageIndex{6}\)). The rib cage includes the 12 thoracic vertebrae and the breastbone (or sternum) as well as 12 pairs of ribs, which are attached at joints to the vertebrae. The ribs are divided into three groups, called true ribs, false ribs, and floating ribs. The top seven pairs of ribs are true ribs. They are attached by cartilage directly to the sternum. The next three pairs of ribs are false ribs. They are attached by cartilage to the ribs above them, rather than directly to the sternum. The lowest two pairs of ribs are floating ribs. They are attached by cartilage to muscles in the abdominal wall. The attachments of false and floating ribs let the lower part of the rib cage expand to accommodate the internal movements of breathing.
thoracic cage
Figure \(\PageIndex{6}\): The rib cage encloses and protects the thoracic cavity. Image used with permission (public domain; U.S. Government via wikimedia.org).
Appendicular Skeleton
Appendicular skeleton diagram
Figure \(\PageIndex{7}\). The appendicular skeleton includes the upper and lower appendages and girdles. Image used with permission (public domain; LadyofHats Mariana Ruiz Villarreal; via wikimedia.org)
The appendicular skeleton, shown in red in Figure \(\PageIndex{7}\), consists of a total of 126 bones. It includes all the bones of the limbs (arms, legs, hands, and feet) as well as the bones of the shoulder (shoulder girdle) and pelvis (pelvic girdle).
Upper Limbs
Each upper limb consists of 30 bones. As shown in Figure \(\PageIndex{8}\), there is one bone, called the humerus, in each of the upper arms, and there are two bones, called the ulna and radius, in each of the lower arms.
The remaining bones of the upper limb are shown in Figure \(\PageIndex{9}\). Each wrist contains eight carpal bones, which are arranged in two rows of four bones each; and each hand contains five metacarpal bones. The bones in the fingers of each hand include 14 phalanges (three in each finger except the thumb, which has two phalanges). The thumb has the unique ability to move into opposition with the palm of the hand and with each of the fingers when they are slightly bent. This allows the hand to handle and manipulate objects such as tools.
Arm Bones
Figure \(\PageIndex{8}\): In the upper limb, the upper arm contains one bone, Humerus, and the lower arm contains two bone, Ulna and Radius. Image used with permission (CC BY3.0; BruceBlaus, 2014; via wikimedia.org)
Human left hand bones with metacarpal numbers and carpal letters
Figure \(\PageIndex{9}\): Bones of the wrist (carpals A-E) and hand (metacarpals 1-5 and phalanges). Image used with permission (public domain; LadyofHats Mariana Ruiz Villarreal via wikimedia.org).
Lower Limbs
Human leg bones labeled
Figure \(\PageIndex{10}\): Bones of the legs. Image used with permission (public domain; Jecowa via wikimedia.org).
Each lower limb consists of 30 bones. As shown in Figure \(\PageIndex{10}\), there is one bone, called the femur, in each of the upper legs, and there are two bones, called the tibia and fibula, in each of the lower legs. The knee cap, or patella, is an additional leg bone at the front of each knee, which is the largest joint in the human body.
The remaining bones of the lower limbs are shown in Figure \(\PageIndex{11}\). Each ankle contains seven tarsal bones (including the talus and calcaneus), and each foot contains five metatarsal bones. The tarsals and metatarsals form the ankle, heel, and arch of the foot. They give the foot strength while allowing flexibility. The bones in the toes of each foot consist of 14 phalanges (three in each toe except the big toe, which has two phalanges)
Foot Anatomy
Figure \(\PageIndex{11}\): Bones of the lower leg (fibula and tibia), ankle (talus), heel (calcaneus), foot (metatarsals), and toes (phalanges). Image used with permission (CC BY 3.0; BruceBlaus, 2014 via wikimedia.org).
Pectoral girdle front diagram
Figure \(\PageIndex{12}\): Bones of the shoulder girdle. Image used with permission (public domain; LadyofHats Mariana Ruiz Villarreal; via wikimedia.org).
The pectoral girdle (also called shoulder girdle) attaches the upper limbs to the trunk of the body. Its connection with the axial skeleton is by muscles alone. This allows a considerable range of motion in the upper limbs. The shoulder girdle consists of just two pairs of bones, with one of each pair on opposite sides of the body (Figure \(\PageIndex{12}\)). There are a right and left clavicles (collarbone) and a right and left scapulae (shoulder blade). The scapula is a pear-shaped flat bone that helps to form the shoulder joint. The clavicle is a long bone that serves as a strut between the shoulder blade and the sternum.
Pelvic Girdle
The pelvic girdle attaches the legs to the trunk of the body and also provides a basin to contain and support the organs of the abdomen. It is connected to the vertebral column of the axial skeleton by ligaments. The pelvic girdle consists of two halves, one half for each leg, but the halves are fused with each other in adults at a joint called the pubic symphysis. Each half of the pelvic girdle includes three bones, as shown in the figure below: the ilium (flaring upper part of the pelvic girdle), pubis (lower front), and ischium (lower back). Each of these bones helps form the acetabulum, which is a depression into which the top of the femur (thighbone) fits. When the body is in a seated position, it rests on protrusions (called tuberosities) of the two ischial bones.
pelvic girdle
Figure \(\PageIndex{13}\)L Bones of the pelvic girdle. (Public domain: IJe at uwo via Wikipedia).
Summary
• The axial skeleton consists of a total of 80 bones. It includes the skull, vertebral column, and rib cage. It also includes the three tiny ossicles in the middle ear and the hyoid bone in the throat.
• The skull provides a bony framework for the head. It consists of 22 different bones: eight in the cranium, which encloses the brain, and 14 in the face, which includes the upper and lower jaw.
• The vertebral column is a flexible, S-shaped column of 33 vertebrae that connects the trunk with the skull and encloses the spinal cord. The vertebrae are divided into five regions: cervical, thoracic, lumbar, sacral, and coccygeal regions. The S shape of the vertebral column allows it to absorb shocks and distribute the weight of the body.
• The rib cage holds and protects the organs of the upper part of the trunk, including the heart and lungs. It includes the 12 thoracic vertebrae, the sternum, and 12 pairs of ribs.
• The appendicular skeleton consists of a total of 126 bones. It includes the bones of the four limbs, shoulder girdle, and pelvic girdle.
• Each upper limb consists of 30 bones. There is one bone, called the humerus, in the upper arm, and two bones, called the ulna and radius, in the lower arm. The wrist contains eight carpal bones, the hand contains five metacarpals, and the fingers consist of 14 phalanges. The thumb is opposable to the palm and fingers of the same hand.
• Each lower limb also consists of 30 bones. There is one bone, called the femur, in the upper leg, and two bones, called the tibia and fibula, in the lower leg. The patella covers the knee joint. The ankle contains seven tarsal bones, and the foot contains five metatarsals. The tarsals and metatarsals form the heel and arch of the foot. The bones in the toes consist of 14 phalanges.
• The shoulder girdle attaches the upper limbs to the trunk of the body. It is connected to the axial skeleton only by muscles, allowing mobility of the upper limbs. Bones of the shoulder girdle include a right and left clavicle and a right and left scapula.
• The pelvic girdle attaches the legs to the trunk of the body and supports the organs of the abdomen. It is connected to the axial skeleton by ligaments. The pelvic girdle consists of two halves that are fused together in adults. Each half consists of three bones: the ilium, pubis, and ischium.
Review
1. What bones are included in the axial skeleton?
2. Identify the two main parts of the skull. How many bones does each part contain?
3. Describe the vertebral column.
4. What are the advantages of an S-shaped vertebral column?
5. What is the rib cage, and what is its function?
6. What bones are included in the appendicular skeleton?
7. How many bones are found in each upper limb? What are they?
8. Identify the bones in each of the lower limbs.
9. What is the shoulder girdle, and why does it allow considerable upper limb mobility?
10. Describe the pelvic girdle and the bones it contains.
11. True or False. False ribs are made of cartilage and are not true rib bones.
12. True or False. The jaw contains two maxillae and one mandible.
13. Describe some of the similarities between the upper limbs and the lower limbs.
14. Explain the advantage of having some ribs that are not attached directly to the sternum.
15. Put the following vertebral regions in order, from the closest to the head to the farthest from the head:
sacral; lumbar; cervical; coccygeal; thoracic
Explore More
Check out this video to learn about the fusion of bones in the skull of newborns here:
To learn more about divisions of the skeletal system, check out this video: | {
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7,263,834,133,153,267,000 | Stomach cancer is one of the most common malignancies in Korea.
Stomach cancer is one of the most common malignancies in Korea. group 1, whereas it had been 1.6% (9/568) in group 2 (beliefs of <0.05 were considered significant Birinapant (TL32711) statistically. Ethics declaration This research was accepted by the institutional critique plank of Centers for Disease Control and Avoidance in Korea. Outcomes Subject features (Desk 1) Desk 1 Overall features of participants within this research The mean age group of the topics was 50.0 yr (range, 20-97 yr). Among the 19,083 topics, 45.4% were man. The approximated 24-hr urine sodium excretion for the whole research population calculated utilizing the Tanaka formula (10) was 144.336.3 mEq/time, and 1,940 (10.2%) topics had <100 mEq/time of sodium excretion. The entire estimated amount of 24-hr urine sodium excretion determined by using the Korean equation was 167.536.3 mEq/day time, and 484 (2.5%) subjects had sodium excretion ideals of <100 mEq/day time. Among the subjects, 99.1% responded the survey on cancer history including belly cancer, colorectal malignancy, liver cancer, and lung malignancy in both men and women, and breast cancer tumor and cervical cancers in women. Of the, 123 (0.65%) topics had a brief history of tummy cancer; at the proper period of the study, 44 (0.23%) people had tummy cancer. General, the topics with background of tummy cancer had been diagnosed 7.76.0 yr to the study preceding; 4 individuals were diagnosed in the Birinapant (TL32711) same calendar year as the study, 9 had been diagnosed the last calendar year, 10 had been diagnosed 2 yr prior, 8 had been diagnosed 3 yr prior, 13 had been diagnosed 4 yr prior, and 78 sufferers had been diagnosed >5 yr prior to the study, 1 of Birinapant (TL32711) whom didn’t know if they had been diagnosed. We executed an analysis from the eating intake of 16,878 (88.4%) topics. The approximated sodium intake was 4.9151.385 g/time (213.760.2 mEq/time), and it had been greater than the estimated worth of 24-hr urine sodium excretion. The association of cancers prevalence with sodium intake approximated with a nutritional questionnaire We evaluated the difference in cancers prevalence regarding to groupings stratified according with their approximated nutritional sodium intake (g/time). The prevalence of most cases of tummy cancer tumor (All), current (Present) situations, and latest (Latest) cases weren’t considerably different among the groupings stratified regarding to nutritional sodium intake (E24INTAKE4). (Fig. 1, worth for E24UNA_T =0.002, worth Birinapant (TL32711) for E24UNA_K=0.005). Desk 4 The characteristics of participants grouped relating to history of belly cancer Variables that were independently associated with the estimated level of 24-hr urine sodium excretion determined by using the Korean equation were age, sex, Rabbit Polyclonal to GRAK current DM, current HTN, BMI, education level, exercise ability, home ownership status, marital status, occupational status, cigarette smoking, SBP, and DBP. We modified the variables, and compared the estimated E24UNA_K ideals according to the presence or absence of a history of belly tumor. As a result, a history of belly cancer was significantly associated with estimated value of 24-hr urine sodium excretion (ANCOVA, colonization. illness is one of the important known risk elements of tummy cancer. responds to adjustments in environmentally friendly sodium focus in that true method that development, cell morphology, success, and virulence aspect expression are changed (25). There have been several Birinapant (TL32711) restrictions of the existing research. First, this is not a potential research, and cancer background was obtained with a questionnaire; as a result, the prevalence may not be as exact as that of a prospective study. Second, we’re able to not eliminate the feasible confounding factors, such as for example infection, which is among the essential risk elements for tummy cancer. To conclude, high salt consumption leads to a higher price of approximated 24-hr urine sodium excretion, which is definitely associated with a history of belly or breast tumor. Notes This paper was supported by the following give(s): Ministry of Food and Drug Security 13162MFDS104. Footnotes This study was supported by a grant (13162MFDS104) in 2013 from your Ministry of Food and Drug Security, Korea. The authors have no conflicts of interest to disclose.. | {
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8,175,020,996,653,897,000 | Home
Radiology Guides Anatomy Physio & Path Medicine Physics Contact
ASTHMA-CAUSES
Respiratory
ASTHMA-CAUSES
1. Host factors (especially genetic susceptibility): atopy is the strongest identifiable predisposing factor for developing lgE-mediated asthma.
2. Environmental factors: exposure to certain environmental agents at critical points in immune development.
3. Triggers are environmental factors that may be the cause of asthma or exacerbate symptoms when the airways are hypersensitive. Triggers can be broadly categorized into 6 areas: allergens, irritants, chemicals, respiratory infections, physical stress, and emotional stress.
4. Other environmental agents are pollution, tobacco smoke, and airborne agents prevalent in certain occupations.
Avatar
REFERENCES
1. Wilkinson, I. (2017). Oxford handbook of clinical medicine. Oxford: Oxford University Press.
2. Hannaman, R. A., Bullock, L., Hatchell, C. A., & Yoffe, M. (2016). Internal medicine review core curriculum, 2017-2018. CO Springs, CO: MedStudy.
3. Image: no reference available.
Ⓒ A. Manickam 2018
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8,386,924,341,939,653,000 | Our Doctor Explains The Best Way To Stop A Panic Attack Fast
People who experience panic attacks may sometimes feel on edge for fear of having an attack in an inopportune place, according to the National Institute of Mental Health. Unlike being stressed or anxious about something, a panic attack can arise without a trigger. Someone having a panic attack will suddenly be overcome by a sense of worry or fear, and this triggers the sympathetic nervous system. Your heart will suddenly race, your breath will quicken, or you could break out into a sweat. Some people might have digestive issues or problems concentrating.
In an exclusive interview with Health Digest, Chief Medical Officer and Physician at One Oak Medical Dr. Jason Singh says the best remedy for stopping a panic attack is to understand why the body is responding the way it does.
"The increase in breathing and heart is the body's mechanism to find more ways to get more oxygen into muscle in case they need to react during this 'fight or flight' response of an anxiety attack," Singh said. "Sweating helps to cool the body. Trembling helps the muscles respond. Nausea/GI issues are because the GI system essentially shuts down since it's not essential in an emergency." Singh also has other strategies to help ease a panic attack.
The grounding technique for panic attacks
During a panic attack, your mind might be racing with uncontrollable thoughts and worries. You might also be flooded with negative memories. In an Instagram reel, Dr. Jason Singh suggests a popular mindfulness technique to engage your parasympathetic nervous system and direct your attention to your senses. Grounding methods such as this 5-4-3-2-1 technique give your mind something else to do rather than allowing these feelings to ruminate (per Therapist Aid).
When you feel a panic attack coming on, name five things you see around you. Then identify four things you can touch, three things you hear, and two things you smell. Finish off this grounding technique by offering some positive advice from your future self that would be useful to you at this moment.
"This tangible pattern will bring your focus to the present–the here and now–with a positive, internal dialogue," he says. "That's what interrupts fearful thoughts."
Other calming strategies for panic attacks
Because a panic attack activates your fight-or-flight response, Dr. Jason Singh says that deep breathing helps to counter the physical effects of a panic attack. "Increased oxygen into the body also lowers heart rate, which signals the body that it does not need to 'rev up' during an attack."
Deep breathing exercises can also train your body to relax when you're not having a panic attack. According to a 2016 study in Perspectives in Psychiatric Care, eight weeks of diaphragmatic breathing practice can reduce overall levels of anxiety and heart rate.
Guided imagery and meditation also serve to redirect your mind from repetitive thoughts to something specific. Meditation works to engage your brain's prefrontal cortex (the organizing part of your brain) rather than your amygdala (your emotional brain).
"Also, there is something called cognitive reappraisal, which is a way to identify thoughts that may be irrational which is triggering the anxiety and then consciously replacing them with more positive and realistic perspectives," Singh said. He adds that sometimes the best way to ground yourself in the present moment is to have strong support from friends and family. | {
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3,160,181,270,772,274,700 | TY - JOUR T1 - <span class="named-content genus-species" id="named-content-1">Bacteroides fragilis</span> Strain ZY-312 Defense against <span class="named-content genus-species" id="named-content-2">Cronobacter sakazakii</span>-Induced Necrotizing Enterocolitis <em>In Vitro</em> and in a Neonatal Rat Model JF - mSystems DO - 10.1128/mSystems.00305-19 VL - 4 IS - 4 SP - e00305-19 AU - Fan, Hongying AU - Chen, Zhenhui AU - Lin, Ruqin AU - Liu, Yangyang AU - Wu, Xianbo AU - Puthiyakunnon, Santhosh AU - Wang, Ye AU - Zhu, Bo AU - Zhang, Qiwei AU - Bai, Yang AU - Zhi, Fachao A2 - Manichanh, Chaysavanh Y1 - 2019/08/27 UR - http://msystems.asm.org/content/4/4/e00305-19.abstract N2 - Cronobacter sakazakii is an important pathogen associated with the development of necrotizing enterocolitis (NEC), infant sepsis, and meningitis. Several randomized prospective clinical trials demonstrated that oral probiotics could decrease the incidence of NEC. Previously, we isolated and characterized a novel probiotic, Bacteroides fragilis strain ZY-312. However, it remains unclear how ZY-312 protects the host from the effects of C. sakazakii infection. To understand the underlying mechanisms triggering the probiotic effects, we tested the hypothesis that there was cross talk between probiotics/probiotics-modulated microbiota and the local immune system, governed by the permeability of the intestinal mucosa, using in vitro and in vivo models for the intestinal permeability. The probiotic effects of ZY-312 on intestinal epithelial cells were first examined, and the results revealed that ZY-312 inhibited C. sakazakii invasion, C. sakazakii-induced dual cell death (pyroptosis and apoptosis), and epithelial barrier dysfunction in vitro and in vivo. The presence of ZY-312 also resulted in decreased expression of an inflammasome (NOD-like receptor family member pyrin domain-containing protein 3 [NLRP3]), caspase-3, and serine protease caspase-1 in a neonatal rat model. Furthermore, ZY-312 significantly modulated the compositions of the intestinal bacterial communities and decreased the relative abundances of Proteobacteria and Gammaproteobacteria but increased the relative abundances of Bacteroides and Bacillus in neonatal rats. In conclusion, our findings have shown for the first time that the probiotic B. fragilis ZY-312 suppresses C. sakazakii-induced NEC by modulating the proinflammatory response and dual cell death (apoptosis and pyroptosis).IMPORTANCE Cronobacter sakazakii is an opportunistic pathogenic bacterium that can cause necrotizing enterocolitis (NEC). However, the mechanism of pathogenicity of C. sakazakii is largely unknown. Here we have now demonstrated that apoptotic and pyroptotic stimuli are effectors of C. sakazakii-induced NEC. Previously, we isolated a novel probiotic strain candidate from fecal samples from healthy infants and characterized it as Bacteroides fragilis strain ZY-312. Functional characterization reveals that ZY-312 inhibited C. sakazakii invasion, restoring epithelial barrier dysfunction, decreasing the expression of inflammatory cytokines, and reducing dual cell death (pyroptosis and apoptosis). Furthermore, the presence of ZY-132 was sufficient to hinder the adverse reaction seen with C. sakazakii in a C. sakazakii-induced NEC model. Taking the results together, our study demonstrated the utility of ZY-312 as a promising probiotic agent for the prevention of NEC. ER - | {
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Hemorrhagic Stroke
Updated: Apr 22, 2019
Author: David S Liebeskind, MD, FAAN, FAHA, FANA; Chief Editor: Andrew K Chang, MD, MS
Overview
Practice Essentials
In hemorrhagic stroke, bleeding occurs directly into the brain parenchyma. The usual mechanism is thought to be leakage from small intracerebral arteries damaged by chronic hypertension. The terms intracerebral hemorrhage and hemorrhagic stroke are used interchangeably in this article and are regarded as separate entities from hemorrhagic transformation of ischemic stroke. See the image below.
Axial noncontrast computed tomography scan of the Axial noncontrast computed tomography scan of the brain of a 60-year-old man with a history of acute onset of left-sided weakness. Two areas of intracerebral hemorrhage are seen in the right lentiform nucleus, with surrounding edema and effacement of the adjacent cortical sulci and right sylvian fissure. Mass effect is present upon the frontal horn of the right lateral ventricle, with intraventricular extension of the hemorrhage.
See Acute Stroke, a Critical Images slideshow, for more information on incidence, presentation, intervention, and additional resources.
Also, see the Vertigo: 5 Case-Based Diagnostic Puzzles slideshow to help recognize diagnostic clues in vertigo cases.
Signs and symptoms
Patients with intracerebral bleeds are more likely than those with ischemic stroke to have headache, altered mental status, seizures, nausea and vomiting, and/or marked hypertension. Even so, none of these findings reliably distinguishes between hemorrhagic and ischemic stroke.
Focal neurologic deficits
The type of deficit depends on the area of brain involved. If the dominant (usually the left) hemisphere is involved, a syndrome consisting of the following may result:
• Right hemiparesis
• Right hemisensory loss
• Left gaze preference
• Right visual field cut
• Aphasia
• Neglect (atypical)
If the nondominant (usually the right) hemisphere is involved, a syndrome consisting of the following may result:
• Left hemiparesis
• Left hemisensory loss
• Right gaze preference
• Left visual field cut
See Clinical Presentation for more detail.
Diagnosis
Laboratory tests should include a complete blood count (CBC), a metabolic panel, and—particularly in patients taking anticoagulants—coagulation studies (ie, prothrombin time or international normalized ratio [INR] and an activated partial thromboplastin time).[1]
Brain imaging is a crucial step in the evaluation of suspected hemorrhagic stroke and must be obtained on an emergent basis. Brain imaging aids diagnosing hemorrhage, and it may identify complications such as intraventricular hemorrhage, brain edema, or hydrocephalus. Either noncontrast computed tomography (NCCT) scanning or magnetic resonance imaging (MRI) is the modality of choice.
See Workup for more detail.
Management
The treatment and management of patients with acute intracerebral hemorrhage depends on the cause and severity of the bleeding. Basic life support, as well as control of bleeding, seizures, blood pressure (BP), and intracranial pressure, are critical. Medications used in the treatment of acute stroke include the following:
• Anticonvulsants - To prevent seizure recurrence
• Antihypertensive agents - To reduce BP and other risk factors of heart disease
• Osmotic diuretics - To decrease intracranial pressure in the subarachnoid space
A potential treatment for hemorrhagic stroke is surgical evacuation of the hematoma. However, the role of surgical treatment for supratentorial intracranial hemorrhage remains controversial. Outcomes in published studies are conflicting.
Endovascular therapy using coil embolization, as an alternative to surgical clipping, has been increasingly employed with great success, although controversy still exists over which treatment is ultimately superior.
See Treatment and Medication for more detail.
Background
Hemorrhagic stroke is less common than ischemic stroke (ie, stroke caused by thrombosis or embolism); epidemiologic studies indicate that only 8-18% of strokes are hemorrhagic.[2] However, hemorrhagic stroke is associated with higher mortality rates than is ischemic stroke. (See Epidemiology.)[3]
Patients with hemorrhagic stroke may present with focal neurologic deficits similar to those of ischemic stroke but tend to be more ill than are patients with ischemic stroke. However, though patients with intracerebral bleeds are more likely to have headache, altered mental status, seizures, nausea and vomiting, and/or marked hypertension.
Brain imaging is a crucial step in the evaluation of suspected hemorrhagic stroke and must be obtained on an emergent basis (see the image below). Brain imaging aids in excluding ischemic stroke, and it may identify complications of hemorrhagic stroke such as intraventricular hemorrhage, brain edema, and hydrocephalus. Either noncontrast computed tomography (NCCT) scanning or magnetic resonance imaging (MRI) is the modality of choice. For more information, see Ischemic Stroke in Emergency Medicine. (See Workup.)
Axial noncontrast computed tomography scan of the Axial noncontrast computed tomography scan of the brain of a 60-year-old man with a history of acute onset of left-sided weakness. Two areas of intracerebral hemorrhage are seen in the right lentiform nucleus, with surrounding edema and effacement of the adjacent cortical sulci and right sylvian fissure. Mass effect is present upon the frontal horn of the right lateral ventricle, with intraventricular extension of the hemorrhage.
Anatomy
Knowledge of cerebrovascular arterial anatomy and the brain regions supplied by the arteries is useful in determining which vessels are involved in acute stroke. Atypical patterns that do not conform to a vascular distribution may indicate another diagnosis, such as venous infarction.
The cerebral hemispheres are supplied by 3 paired major arteries: the anterior, middle, and posterior cerebral arteries. The anterior and middle cerebral arteries are responsible for the anterior circulation and arise from the supraclinoid internal carotid arteries. The posterior cerebral arteries arise from the basilar artery and form the posterior circulation, which also supplies the thalami, brainstem, and cerebellum. The angiograms in the images below demonstrate some portions of the circulation involved in hemorrhagic strokes.
Frontal view of a cerebral angiogram with selectiv Frontal view of a cerebral angiogram with selective injection of the left internal carotid artery illustrates the anterior circulation. The anterior cerebral artery consists of the A1 segment proximal to the anterior communicating artery with the A2 segment distal to it. The middle cerebral artery can be divided into 4 segments: the M1 (horizontal segment) extends to the limen insulae and gives off lateral lenticulostriate branches, the M2 (insular segment), M3 (opercular branches), and M4 (distal cortical branches on the lateral hemispheric convexities).
Lateral view of a cerebral angiogram illustrates t Lateral view of a cerebral angiogram illustrates the branches of the anterior cerebral artery (ACA) and sylvian triangle. The pericallosal artery has been described as arising distal to the anterior communicating artery or distal to the origin of the callosomarginal branch of the ACA. The segmental anatomy of the ACA has been described as follows: (1) the A1 segment extends from the internal carotid artery (ICA) bifurcation to the anterior communicating artery, (2) A2 extends to the junction of the rostrum and genu of the corpus callosum, (3) A3 extends into the bend of the genu of the corpus callosum, and (4) A4 and A5 extend posteriorly above the callosal body and superior portion of the splenium. The sylvian triangle overlies the opercular branches of the middle cerebral artery, with the apex representing the sylvian point.
Frontal projection from a right vertebral artery a Frontal projection from a right vertebral artery angiogram illustrates the posterior circulation. The vertebral arteries join to form the basilar artery. The posterior inferior cerebellar arteries (PICA) arise from the distal vertebral arteries. The anterior inferior cerebellar arteries (AICA) arise from the proximal basilar artery. The superior cerebellar arteries (SCA) arise distally from the basilar artery before its bifurcation into the posterior cerebral arteries.
Pathophysiology
In intracerebral hemorrhage, bleeding occurs directly into the brain parenchyma. The usual mechanism is thought to be leakage from small intracerebral arteries damaged by chronic hypertension. Other mechanisms include bleeding diatheses, iatrogenic anticoagulation, cerebral amyloidosis, and cocaine abuse.
Intracerebral hemorrhage has a predilection for certain sites in the brain, including the thalamus, putamen, cerebellum, and brainstem. In addition to the area of the brain injured by the hemorrhage, the surrounding brain can be damaged by pressure produced by the mass effect of the hematoma. A general increase in intracranial pressure may occur.
Subarachnoid hemorrhage
The pathologic effects of subarachnoid hemorrhage (SAH) on the brain are multifocal. SAH results in elevated intracranial pressure and impairs cerebral autoregulation. These effects can occur in combination with acute vasoconstriction, microvascular platelet aggregation, and loss of microvascular perfusion, resulting in profound reduction in blood flow and cerebral ischemia.[4] See the images below.
Noncontrast computed tomography (CT) scanning was Noncontrast computed tomography (CT) scanning was performed emergently in a 71-year-old man who presented with acute onset of severe headache and underwent rapid neurologic deterioration requiring intubation. The noncontrast CT scan (left image) demonstrates diffuse, high-density subarachnoid hemorrhage in the basilar cisterns and both Sylvian fissures. There is diffuse loss of gray-white differentiation. The fluid-attenuated inversion-recovery (FLAIR) image (right) demonstrates high signal throughout the cortical sulci and in the basilar cisterns, as well as in the dependent portions of the ventricles. FLAIR is highly sensitive to acute subarachnoid hemorrhage; the suppression of high cerebrospinal fluid signal aids in making subarachnoid hemorrhage more conspicuous than do conventional magnetic resonance imaging sequences.
Computed tomographic angiography examination and s Computed tomographic angiography examination and subsequent cerebral angiography were performed in 71-year-old man who presented with acute onset of severe headache and underwent rapid neurologic deterioration. Multiple aneurysms were identified, including a 9-mm aneurysm at the junction of the anterior cerebral and posterior communicating arteries seen on this lateral view of an internal carotid artery injection. Balloon-assisted coil embolization was performed.
Lateral view of a selective injection of the left Lateral view of a selective injection of the left internal carotid artery demonstrates a microcatheter passing distal to the aneurysm neck. This lateral view from an angiogram performed during balloon-assisted coil embolization demonstrates significantly diminished filling of the aneurysm.
Etiology
The etiologies of stroke are varied, but they can be broadly categorized into ischemic or hemorrhagic. Approximately 80–87% of strokes are from ischemic infarction caused by thrombotic or embolic cerebrovascular occlusion. Intracerebral hemorrhages account for most of the remainder of strokes, with a smaller number resulting from aneurysmal subarachnoid hemorrhage.[5, 6, 7, 8]
In 20–40% of patients with ischemic infarction, hemorrhagic transformation may occur within 1 week after ictus.[9, 10]
Differentiating between the different types of stroke is an essential part of the initial workup of patients with stroke, as the subsequent management of each disorder will be vastly different.
Risk factors
The risk of hemorrhagic stroke is increased with the following factors:
• Advanced age
• Hypertension (up to 60% of cases)
• Previous history of stroke
• Alcohol abuse
• Use of illicit drugs (eg, cocaine, other sympathomimetic drugs)
Causes of hemorrhagic stroke include the following[8, 9, 11, 12, 13] :
• Hypertension
• Cerebral amyloidosis
• Coagulopathies
• Anticoagulant therapy
• Thrombolytic therapy for acute myocardial infarction (MI) or acute ischemic stroke (can cause iatrogenic hemorrhagic transformation)
• Arteriovenous malformation (AVM), aneurysms, and other vascular malformations (venous and cavernous angiomas)
• Vasculitis
• Intracranial neoplasm
Hypertension
The most common etiology of primary hemorrhagic stroke (intracerebral hemorrhage) is hypertension. At least two thirds of patients with primary intraparenchymal hemorrhage are reported to have preexisting or newly diagnosed hypertension. Hypertensive small-vessel disease results from tiny lipohyalinotic aneurysms that subsequently rupture and result in intraparenchymal hemorrhage. Typical locations include the basal ganglia, thalami, cerebellum, and pons.
Amyloidosis
Cerebral amyloidosis affects people who are elderly and may cause up to 10% of intracerebral hemorrhages. Rarely, cerebral amyloid angiopathy can be caused by mutations in the amyloid precursor protein and is inherited in an autosomal dominant fashion.
Coagulopathies
Coagulopathies may be acquired or inherited. Liver disease can result in a bleeding diathesis. Inherited disorders of coagulation such as factor VII, VIII, IX, X, and XIII deficiency can predispose to excessive bleeding, and intracranial hemorrhage has been seen in all of these disorders.
Anticoagulant therapy
Anticoagulant therapy is especially likely to increase hemorrhage risk in patients who metabolize warfarin inefficiently. Warfarin metabolism is influenced by polymorphism in the CYP2C9 genes. Three known variants have been described. CYP2C9*1 is the normal variant and is associated with typical response to dosage of warfarin. Variations *2 and *3 are relatively common polymorphisms that reduce the efficiency of warfarin metabolism.[14]
Arteriovenous malformations
Numerous genetic causes may predispose to AVMs in the brain, although AVMs are generally sporadic. Polymorphisms in the IL6 gene increase susceptibility to a number of disorders, including AVM. Hereditary hemorrhagic telangiectasia (HHT), previously known as Osler-Weber-Rendu syndrome, is an autosomal dominant disorder that causes dysplasia of the vasculature. HHT is caused by mutations in ENG, ACVRL1, or SMAD4 genes. Mutations in SMAD4 are also associated with juvenile polyposis, so this must be considered when obtaining the patient’s history.
HHT is most frequently diagnosed when patients present with telangiectasias on the skin and mucosa or with chronic epistaxis from AVMs in the nasal mucosa. Additionally, HHT can result in AVMs in any organ system or vascular bed. AVM in the gastrointestinal tract, lungs, and brain are the most worrisome, and their detection is the mainstay of surveillance for this disease.
Cholesterol
A study of almost 28,000 women over a period of approximately 20 years found that women with very low levels of low-density lipoprotein cholesterol (LDL-C) (< 70 mg/dL) may be more than twice as likely to have a hemorrhagic stroke than women with higher levels (100–130 mg/dL).[15]
Aneurysms and subarachnoid hemorrhage
The most common cause of atraumatic hemorrhage into the subarachnoid space is rupture of an intracranial aneurysm. Aneurysms are focal dilatations of arteries, with the most frequently encountered intracranial type being the berry (saccular) aneurysm. Aneurysms may less commonly be related to altered hemodynamics associated with AVMs, collagen vascular disease, polycystic kidney disease, septic emboli, and neoplasms.
Nonaneurysmal perimesencephalic subarachnoid hemorrhage may also be seen. This phenomenon is thought to arise from capillary or venous rupture. It has a less severe clinical course and, in general, a better prognosis.
Berry aneurysms are most often isolated lesions whose formation results from a combination of hemodynamic stresses and acquired or congenital weakness in the vessel wall. Saccular aneurysms typically occur at vascular bifurcations, with more than 90% occurring in the anterior circulation. Common sites include the following:
• The junction of the anterior communicating arteries and anterior cerebral arteries—most commonly, the middle cerebral artery (MCA) bifurcation
• The supraclinoid internal carotid artery at the origin of the posterior communicating artery
• The bifurcation of the internal carotid artery (ICA)
Genetic causes of aneurysms
Intracranial aneurysms may result from genetic disorders. Although rare, several families have been described that have a predisposition—inherited in an autosomal dominant fashion—to intracranial berry aneurysms. A number of genes, all categorized as ANIB genes, are associated with this predisposition. Presently, ANIB1 through ANIB11 are known.
Autosomal dominant polycystic kidney disease (ADPKD) is another cause of intracranial aneurysm. Families with ADPKD tend to show phenotypic similarity with regard to intracranial hemorrhage or asymptomatic berry aneurysms.[16]
Loeys-Dietz syndrome (LDS) consists of craniofacial abnormalities, craniosynostosis, marked arterial tortuosity, and aneurysms and is inherited in an autosomal dominant manner. Although intracranial aneurysms occur in LDS of all types, saccular intracranial aneurysms are a prominent feature of LDS type IC, which is caused by mutations in the SMAD3 gene.[17]
Ehlers-Danlos syndrome is a group of inherited disorders of the connective tissue that feature hyperextensibility of the joints and changes to the skin, including poor wound healing, fragility, and hyperextensibility. However, Ehlers-Danlos vascular type (type IV) also is known to cause spontaneous rupture of hollow viscera and large arteries, including arteries in the intracranial circulation.
Patients with Ehlers-Danlos syndrome may also have mild facial findings, including lobeless ears, a thin upper lip, and a thin, sharp nose. The distal fingers may appear prematurely aged (acrogeria). In the absence of a suggestive family history, it is difficult to separate Ehlers-Danlos vascular type from other forms of Ehlers-Danlos. Ehlers-Danlos vascular type is caused by mutations in the COL3A1 gene; it is inherited in an autosomal dominant manner.
See Genetic and Inflammatory Mechanisms in Stroke, as well as Blood Dyscrasias and Stroke. Information on metabolic diseases and stroke can be found in the following articles:
• Methylmalonic Acidemia
• Homocystinuria/Homocysteinemia
• Fabry Disease
• MELAS – Mitochondrial Encephalomyopathy, Lactic Acidosis, Strokelike Episodes
• Hyperglycemia/Hypoglycemia
Hemorrhagic transformation of ischemic stroke
Hemorrhagic transformation represents the conversion of a bland infarction into an area of hemorrhage. Proposed mechanisms for hemorrhagic transformation include reperfusion of ischemically injured tissue, either from recanalization of an occluded vessel or from collateral blood supply to the ischemic territory or disruption of the blood-brain barrier. With disruption of the blood-brain barrier, red blood cells extravasate from the weakened capillary bed, producing petechial hemorrhage or frank intraparenchymal hematoma.[8, 9, 18] (For more information, see Reperfusion Injury in Stroke.)
Hemorrhagic transformation of an ischemic infarct occurs within 2–14 days postictus, usually within the first week. It is more commonly seen following cardioembolic strokes and is more likely with larger infarct size.[8, 10, 19] Hemorrhagic transformation is also more likely following administration of tissue plasminogen activator (tPA) in patients whose noncontrast computed tomography (CT) scans demonstrate areas of hypodensity.[18, 20, 21] See the image below.
Noncontrast computed tomography scan (left) obtain Noncontrast computed tomography scan (left) obtained in a 75-year-old man who was admitted for stroke demonstrates a large right middle cerebral artery distribution infarction with linear areas of developing hemorrhage. These become more confluent on day 2 of hospitalization (middle image), with increased mass effect and midline shift. There is massive hemorrhagic transformation by day 6 (right), with increased leftward midline shift and subfalcine herniation. Obstructive hydrocephalus is also noted, with dilatation of the lateral ventricles, likely due to compression of the foramen of Monroe. Intraventricular hemorrhage is also noted layering in the left occipital horn. Larger infarctions are more likely to undergo hemorrhagic transformation and are one contraindication to thrombolytic therapy.
Epidemiology
Occurrence in the United States
Each year in the United States, approximately 795,000 people experience new or recurrent stroke. Of these, approximately 610,000 represent initial attacks, and 185,000 represent recurrent strokes. Epidemiologic studies indicate that approximately 87% of strokes in the United States are ischemic, 10% are secondary to intracerebral hemorrhage, and another 3% may be secondary to subarachnoid hemorrhage.[5, 22]
A 2010 retrospective review from a stroke center found that 40.9% of the 757 patients in the study had suffered hemorrhagic strokes.[23] The researchers speculate that improved availability and implementation of computed tomography (CT) scanning may have unmasked a previous underestimation of the actual percentage of hemorrhagic strokes, or increased use of antiplatelet agents and warfarin may have led to a higher incidence of hemorrhage. Alternatively, this higher rate may represent referral bias of patients with intracerebral hemorrhages to medical centers with neurosurgical capabilities.
The incidence of stroke varies with age, sex, ethnicity, and socioeconomic status. For example, American Heart Association (AHA) researchers found that rates of intracerebral hemorrhage are higher in Mexican Americans, Latin Americans, blacks, Native Americans, Japanese people, and Chinese people than they are in whites.[5]
Flaherty et al found that excess risk of intracranial hemorrhage in African Americans is largely attributable to higher hemorrhage rates in young and middle-aged persons, particularly for deep cerebral and brainstem locations. Hypertension is the predominant risk factor.[24]
International occurrence
According to the World Health Organization (WHO), 15 million people suffer stroke worldwide each year. Of these, 5 million die and another 5 million are left permanently disabled.[25]
The global incidence of stroke has at least a modest variation from nation to nation, suggesting the importance of genetics and environmental factors, such as disparities in access to health care in developing countries. The age-adjusted incidence of total strokes per 1000 person-years for people 55 years or older has been reported in the range of 4.2 to 6.5. The highest incidences have been reported in Russia, Ukraine, and Japan.
In a prospective, population-based registry study from Italy, the crude annual incidence rate of intracerebral hemorrhage was 36.9 per 100,000 population. When standardized to the 2006 European population, the rate was 32.9 per 100,000 population; standardized to the world population, the rate was 15.9 per 100,000 population.[26]
Overall, the incidence of acute stroke has demonstrated a constant decline over the past several decades, most notably during the 1970s-1990s, although in recent years the rate trend has begun to plateau. However, the increased survival among stroke victims will place an increased demand on health-care systems globally.[8, 27]
Stroke subtypes also vary greatly in different parts of the world and between different races. For example, the proportion of hemorrhagic strokes may be higher in certain populations, such as the Chinese population, in which it has been reported to be up to 39.4%, and the Japanese, in which it is reportedly up to 38.7%.[2, 27]
Prognosis
The prognosis in patients with hemorrhagic stroke varies depending on the severity of stroke and the location and the size of the hemorrhage. Lower Glasgow Coma Scale (GCS) scores are associated with poorer prognosis and higher mortality rates. A larger volume of blood at presentation is also associated with a poorer prognosis. Growth of the hematoma volume is associated with a poorer functional outcome and increased mortality rate.
The intracerebral hemorrhage score is the most commonly used instrument for predicting outcome in hemorrhagic stroke. The score is calculated as follows:
• GCS score 3–4: 2 points
• GCS score 5–12: 1 point
• GCS score 13–15: 0 points
• Age ≥80 years: Yes, 1 point; no, 0 points
• Infratentorial origin: Yes, 1 point; no, 0 points
• Intracerebral hemorrhage volume ≥30 cm3: 1 point
• Intracerebral hemorrhage volume < 30 cm3: 0 points
• Intraventricular hemorrhage: Yes, 1 point; no, 0 points
In a study by Hemphill et al, all patients with an Intracerebral Hemorrhage Score of 0 survived, and all of those with a score of 5 died; 30-day mortality increased steadily with the Score.[28]
Other prognostic factors include the following:
• Nonaneurysmal perimesencephalic stroke has a less severe clinical course and, in general, a better prognosis
• The presence of blood in the ventricles is associated with a higher mortality rate; in one study, the presence of intraventricular blood at presentation was associated with a mortality increase of more than 2-fold
• Patients with oral anticoagulation-associated intracerebral hemorrhage have higher mortality rates and poorer functional outcomes
In studies, withdrawal of medical support or issuance of Do Not Resuscitate (DNR) orders within the first day of hospitalization predict poor outcome independent of clinical factors. Because limiting care may adversely impact outcome, American Heart Association/American Stroke Association (AHA/ASA) guidelines suggest that new DNR orders should probably be postponed until at least the second full day of hospitalization. Patients with DNRs should be given all other medical and surgical treatment, unless the DNR explicitly says otherwise.[1]
For more information, see Motor Recovery in Stroke.
Presentation
History
Obtaining an adequate history includes determining the onset and progression of symptoms, as well as assessing for risk factors and possible causative events.
A history of trauma, even if minor, may be important, as extracranial arterial dissections can result in ischemic stroke.
Hemorrhagic versus ischemic stroke
Symptoms alone are not specific enough to distinguish ischemic from hemorrhagic stroke. However, generalized symptoms, including nausea, vomiting, and headache, as well as an altered level of consciousness, may indicate increased intracranial pressure and are more common with hemorrhagic strokes and large ischemic strokes.
Seizures are more common in hemorrhagic stroke than in the ischemic kind. Seizures occur in up to 28% of hemorrhagic strokes, generally at the onset of the intracerebral hemorrhage or within the first 24 hours.
Focal neurologic deficits
The neurologic deficits reflect the area of the brain typically involved, and stroke syndromes for specific vascular lesions have been described. Focal symptoms of stroke include the following:
• Weakness or paresis that may affect a single extremity, one half of the body, or all 4 extremities
• Facial droop
• Monocular or binocular blindness
• Blurred vision or visual field deficits
• Dysarthria and trouble understanding speech
• Vertigo or ataxia
• Aphasia
Symptoms of subarachnoid hemorrhage may include the following:
• Sudden onset of severe headache
• Signs of meningismus with nuchal rigidity
• Photophobia and pain with eye movements
• Nausea and vomiting
• Syncope - Prolonged or atypical
The most common clinical scoring systems for grading aneurysmal subarachnoid hemorrhage are the Hunt and Hess grading scheme and the World Federation of Neurosurgeons (WFNS) grading scheme, which incorporates the Glasgow Coma Scale. The Fisher Scale incorporates findings from noncontrast computed tomography (NCCT) scans.
Physical Examination
The assessment in patients with possible hemorrhagic stroke includes vital signs; a general physical examination that focuses on the head, heart, lungs, abdomen, and extremities; and a thorough but expeditious neurologic examination.[1]
Hypertension (particularly systolic blood pressure [BP] greater than 220 mm Hg) is commonly a prominent finding in hemorrhagic stroke. Higher initial BP is associated with early neurologic deterioration, as is fever.[1]
An acute onset of neurologic deficit, altered level of consciousness/mental status, or coma is more common with hemorrhagic stroke than with ischemic stroke. Often, this is caused by increased intracranial pressure. Meningismus may result from blood in the subarachnoid space.
Examination results can be quantified using various scoring systems. These include the Glasgow Coma Scale (GCS), the Intracerebral Hemorrhage Score (which incorporates the GCS; see Prognosis), and the National Institutes of Health Stroke Scale.
Focal neurologic deficits
The type of deficit depends upon the area of brain involved. If the dominant hemisphere (usually the left) is involved, a syndrome consisting of the following may result:
• Right hemiparesis
• Right hemisensory loss
• Left gaze preference
• Right visual field cut
• Aphasia
• Neglect (atypical)
If the nondominant (usually the right) hemisphere is involved, a syndrome consisting of the following may result:
• Left hemiparesis
• Left hemisensory loss
• Right gaze preference
• Left visual field cut
Nondominant hemisphere syndrome may also result in neglect when the patient has left-sided hemi-inattention and ignores the left side.
If the cerebellum is involved, the patient is at high risk for herniation and brainstem compression. Herniation may cause a rapid decrease in the level of consciousness and may result in apnea or death.
Specific brain sites and associated deficits involved in hemorrhagic stroke include the following:
• Putamen - Contralateral hemiparesis, contralateral sensory loss, contralateral conjugate gaze paresis, homonymous hemianopia, aphasia, neglect, or apraxia
• Thalamus - Contralateral sensory loss, contralateral hemiparesis, gaze paresis, homonymous hemianopia, miosis, aphasia, or confusion
• Lobar - Contralateral hemiparesis or sensory loss, contralateral conjugate gaze paresis, homonymous hemianopia, abulia, aphasia, neglect, or apraxia
• Caudate nucleus - Contralateral hemiparesis, contralateral conjugate gaze paresis, or confusion
• Brainstem - Quadriparesis, facial weakness, decreased level of consciousness, gaze paresis, ocular bobbing, miosis, or autonomic instability
• Cerebellum – Ipsilateral ataxia, facial weakness, sensory loss; gaze paresis, skew deviation, miosis, or decreased level of consciousness
Other signs of cerebellar or brainstem involvement include the following:
• Gait or limb ataxia
• Vertigo or tinnitus
• Nausea and vomiting
• Hemiparesis or quadriparesis
• Hemisensory loss or sensory loss of all 4 limbs
• Eye movement abnormalities resulting in diplopia or nystagmus
• Oropharyngeal weakness or dysphagia
• Crossed signs (ipsilateral face and contralateral body)
Many other stroke syndromes are associated with intracerebral hemorrhage, ranging from mild headache to neurologic devastation. At times, a cerebral hemorrhage may present as a new-onset seizure.
DDx
Diagnostic Considerations
Intracerebral hemorrhage may be clinically indistinguishable from ischemic stroke, and a thorough history and physical examination are important. An acute onset of neurologic deficit, altered level of consciousness/mental status, or coma is more common with hemorrhagic stroke than with ischemic stroke. A history of trauma, even if minor, may be important, as extracranial arterial dissections can result in ischemic stroke.
Seizures are more common in hemorrhagic stroke than in ischemic stroke and occur in up to 28% of hemorrhagic strokes, generally at the onset of the intracerebral hemorrhage or within the first 24 hours. Postictal (Todd) paralysis and hyperosmolality should also be considered.
Differential Diagnoses
Workup
Laboratory Studies
Laboratory tests should include a complete blood count, a metabolic panel, and—particularly in patients taking anticoagulants—coagulation studies (ie, prothrombin time or international normalized ratio [INR] and an activated partial thromboplastin time).[1]
Imaging Studies
Brain imaging is a crucial step in the evaluation of suspected hemorrhagic stroke and must be obtained on an emergent basis. Brain imaging aids diagnosing hemorrhage, and it may identify complications such as intraventricular hemorrhage, brain edema, or hydrocephalus. Either noncontrast computed tomography (NCCT) scanning or magnetic resonance imaging (MRI) is the modality of choice.
Computed tomography (CT)-scan studies can also be performed in patients who are unable to tolerate a magnetic resonance examination or who have contraindications to MRI, including pacemakers, aneurysm clips, or other ferromagnetic materials in their bodies. Additionally, CT-scan examination is more easily accessible for patients who require special equipment for life support. See the image below.
Noncontrast computed tomography scan of the brain Noncontrast computed tomography scan of the brain (left) demonstrates an acute hemorrhage in the left gangliocapsular region, with surrounding white matter hypodensity consistent with vasogenic edema. T2-weighted axial magnetic resonance imaging scan (middle image) again demonstrates the hemorrhage, with surrounding high-signal edema. The coronal gradient-echo image (right) demonstrates susceptibility related to the hematoma, with markedly low signal adjacent the left caudate head. Gradient-echo images are highly sensitive for blood products.
CT angiography and contrast-enhanced CT scanning may be considered for helping identify patients at risk for hematoma expansion. Extravasation of contrast within the hematoma indicates high risk.
When clinical or radiologic findings suggest an underlying structural lesion, useful techniques include CT angiography, CT venography, contrast-enhanced CT scanning, contrast-enhanced MRI, magnetic resonance angiography (MRA), or magnetic resonance venography.[1]
Conventional angiography is the gold standard in evaluating for cerebrovascular disease and for providing less-invasive endovascular interventions. This modality can be performed to clarify equivocal findings or to confirm and treat disease seen on MRA, CTA, transcranial Doppler, or neck ultrasonograms. However, Zhu et al found that in patients with spontaneous intracranial hemorrhage, angiographic yield was significantly lower in patients older than 45 years and those who had preexisting hypertension.[29]
Although the traditional approach to excluding underlying vascular abnormalities in patients with spontaneous intracerebral hemorrhage is to use digital subtraction angiography (DSA) in the acute and subacute phases, Wong et al found that MRA was able to detect most structural vascular abnormalities in the subacute phase in most patients. Consequently, they recommend MRA as the screening test.
Treatment
Approach Considerations
The treatment and management of patients with acute intracerebral hemorrhage depends on the cause and severity of the bleeding. Basic life support, as well as control of bleeding, seizures, blood pressure (BP), and intracranial pressure, are critical. Medications used in the treatment of acute stroke include the following:
• Anticonvulsants - To prevent seizure recurrence
• Antihypertensive agents - To reduce BP and other risk factors of heart disease
• Osmotic diuretics - To decrease intracranial pressure in the subarachnoid space
Management begins with stabilization of vital signs. Perform endotracheal intubation for patients with a decreased level of consciousness and poor airway protection. Intubate and hyperventilate if intracranial pressure is elevated, and initiate administration of mannitol for further control. Rapidly stabilize vital signs, and simultaneously acquire an emergent computed tomography (CT) scan. Glucose levels should be monitored, with normoglycemia recommended.[1] Antacids are used to prevent associated gastric ulcers.
No effective targeted therapy for hemorrhagic stroke exists yet. Studies of recombinant factor VIIa (rFVIIa) have yielded disappointing results. Evacuation of hematoma, either via open craniotomy or endoscopy, may be a promising ultra-early-stage treatment for intracerebral hemorrhage that may improve long-term prognosis.
A combined analysis of INTERACT (Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial) 1 and 2 suggested that in patients with intracerebral hemorrhage, intensive BP reduction early in their treatment lessens the absolute growth of hematomas, with the effect being especially pronounced in patients who have undergone prior antithrombotic therapy.[30]
The study involved 1310 patients who had undergone repeat 24-hour CT scans, including 665 who received intensive BP reduction therapy (target BP < 140 mm Hg systolic) and 645 controls (target BP < 180 mm Hg systolic).[30] A total of 235 patients in the intensive reduction and control groups had received antithrombotic medication prior to intracerebral hemorrhage.
The investigators found that, in patients who had not had prior antithrombotic therapy, hematoma volume increased 1.1 mL on repeat CT scan in those who underwent intensive BP reduction, compared with 2.4 mL in controls.[30] In patients who had previously taken antithrombotics, however, the difference between the intensive-reduction and control groups was much greater, with the increase in hematoma volume being 3.4 mL in the intensive-reduction patients and 8.1 mL in the controls.
Management of Seizures
Early seizure activity occurs in 4-28% of patients with intracerebral hemorrhage; these seizures are often nonconvulsive.[31, 32] According to American Heart Association/American Stroke Association (AHA/ASA) 2010 guidelines for the management of spontaneous intracerebral hemorrhage, patients with clinical seizures or electroencephalographic (EEG) seizure activity accompanied by a change in mental status should be treated with antiepileptic drugs.[1]
Patients for whom treatment is indicated should immediately receive a benzodiazepine, such as lorazepam or diazepam, for rapid seizure control. This should be accompanied by phenytoin or fosphenytoin loading for longer-term control.
Prophylaxis
The utility of prophylactic anticonvulsant medication remains uncertain. In prospective and population-based studies, clinical seizures have not been associated with worse neurologic outcome or mortality. Indeed, 2 studies have reported worse outcomes in patients who did not have a documented seizure but who received antiepileptic drugs (primarily phenytoin).[1]
The 2010 AHA/ASA guidelines do not offer recommendations on prophylactic anticonvulsants, but suggest that continuous EEG monitoring is probably indicated in patients with intracranial hemorrhage whose mental status is depressed out of proportion to the degree of brain injury
Prophylactic anticonvulsant therapy has been recommended in patients with lobar hemorrhages to reduce the risk of early seizures. One large, single-center study showed that prophylactic antiepileptic drugs significantly reduced the number of clinical seizures in these patients.[31]
In addition, AHA/ASA guidelines from 2012 suggest that prophylactic anticonvulsants may be considered for patients with aneurysmal subarachnoid hemorrhage. In such cases, however, anticonvulsant use should generally be limited to the immediate post-hemorrhagic period. Routine long-term use is not recommended, but it may be considered in patients with a prior seizure history, intracerebral hematoma, intractable hypertension, or infarction or aneurysm at the middle cerebral artery.[33]
Blood Pressure Control
No controlled studies have defined optimum BP levels for patients with acute hemorrhagic stroke, but greatly elevated BP is thought to lead to rebleeding and hematoma expansion. Stroke may result in loss of cerebral autoregulation of cerebral perfusion pressure.
Intensive BP reduction (target BP < 140 mm Hg systolic) early in the treatment of patients with intracerebral hemorrhage appears to lessen the absolute growth of hematomas, particularly in patients who have received previous antithrombotic therapy, according to a combined analysis of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials 1 and 2 (INTERACT).[30]
Suggested agents for use in the acute setting are beta blockers (eg, labetalol) and angiotensin-converting enzyme inhibitors (ACEIs) (eg, enalapril). For more refractory hypertension, agents such as nicardipine and hydralazine are used. Avoid nitroprusside because it may raise intracranial pressure.
The 2010 AHA/ASA guidelines acknowledge that evidence for the efficacy of managing BP in hemorrhagic stroke is currently incomplete. With that caveat, the AHA/ASA recommendations for treating elevated BP are as follows[1] :
• If systolic BP is over 200 mm Hg or mean arterial pressure (MAP) is over 150 mm Hg, then consider aggressive reduction of BP with continuous IV infusion; check BP every 5 minutes
• If systolic BP is over 180 mm Hg or MAP is over 130 mm Hg and intracranial pressure may be elevated, then consider monitoring intracranial pressure and reducing BP using intermittent or continuous intravenous medications, while maintaining a cerebral perfusion pressure of 60 mm Hg or higher
• If systolic BP is over 180 or MAP is over 130 mm Hg and there is no evidence of elevated intracranial pressure, then consider modest reduction of BP (target MAP of 110 mm Hg or target BP of 160/90 mm Hg) using intermittent or continuous intravenous medications to control it, and perform clinical reexamination of the patient every 15 minutes
• In patients presenting with a systolic BP of 150 to 220 mm Hg, acute lowering of systolic BP to 140 mm Hg is probably safe
For patients with aneurysmal subarachnoid hemorrhage, the 2012 AHA/ASA guidelines recommend lowering BP below 160 mm Hg acutely to reduce rebleeding.[33]
A 2017 joint practice guideline from the American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP) calls for physicians to start treatment for patients who have persistent systolic blood pressure at or above 150 mm Hg to achieve a target of less than 150 mm Hg to reduce risk for stroke, cardiac events, and death.[34]
The ongoing Antihypertensive Treatment in Acute Cerebral Hemorrhage-II (ATACH-II) phase 3 randomized clinical trial is designed to determine whether the likelihood of death or disability at 3 months after spontaneous supratentorial intracerebral hemorrhage is lower when systolic BP has been reduced to 180 mm Hg or below or to 140 mm Hg or below. In ATACH-II, intravenous nicardipine is started within 3 hours of stroke onset and continued for the next 24 hours.
Intracranial Pressure Control
Elevated intracranial pressure may result from the hematoma itself, from surrounding edema, or from both. The frequency of increased intracranial pressure in patients with intracerebral hemorrhage is not known.
Elevate the head of the bed to 30°. This improves jugular venous outflow and lowers intracranial pressure. The head should be midline and not turned to the side. Provide analgesia and sedation as needed. Antacids are used to prevent gastric ulcers associated with intracerebral hemorrhage.
More aggressive therapies, such as osmotic therapy (ie, mannitol, hypertonic saline), barbiturate anesthesia, and neuromuscular blockage, generally require concomitant monitoring of intracranial pressure and BP with an intracranial pressure monitor to maintain adequate cerebral perfusion pressure of greater than 70 mm Hg. A randomized, controlled study of mannitol in intracerebral hemorrhage failed to demonstrate any difference in disability or death at 3 months.[35]
Hyperventilation (partial pressure of carbon dioxide [PaCO2] of 25 to 30-35 mm Hg) is not recommended, because its effect is transient, it decreases cerebral blood flow, and it may result in rebound elevated intracranial pressure.[3] Glucocorticoids are not effective and result in higher rates of complications with poorer outcomes.
Hemostatic Therapy
The use of hemostatic therapy with rFVIIa to stop ongoing hemorrhage or prevent hematoma expansion has generated much interest. However, research to date has failed to support this off-label use of rFVIIa.[36, 37, 38]
A preliminary study of treatment rFVIIa demonstrated reduced mortality and improved functional outcomes. Unfortunately, the results of a subsequent randomized trial that was larger than the preliminary study revealed no overall benefit from treatment; hemostatic therapy with rFVIIa reduced growth of the hematoma but did not improve survival or functional outcome.[39]
Diringer et al found that a higher dose of rFVIIa was associated with a small increase in the risk of arterial thromboembolic events in patients who presented less than 3 hours after spontaneous intracerebral hemorrhage. Arterial events were also associated with the presence of cardiac or cerebral ischemia at presentation, with advanced age, and with antiplatelet use.[40]
The investigators also found that with the use of 20 or 80 mcg/kg rFVIIa, the rates of venous events were similar to those with placebo.
Treatment of Anticoagulation-associated Intracranial Hemorrhage
Patients on warfarin have an increased incidence of hemorrhagic stroke. Morbidity and mortality for warfarin-associated bleeding is high, with over one half of patients dying within 30 days. Most episodes occur with a therapeutic international normalized ratio (INR), but overanticoagulation is associated with an even greater risk of bleeding.
The need to reverse warfarin anticoagulation is a true medical emergency, and reversal must be accomplished as quickly as possible to prevent further hematoma expansion. Options for reversal therapy include the following:
• Intravenous vitamin K
• Fresh frozen plasma (FFP)
• Prothrombin complex concentrates (PCC)
• rFVIIa
FFP versus PCC
Because vitamin K requires more than 6 hours to normalize the INR, it should be administered with either FFP or PCC. FFP is the standard of care in the United States[41] ; however, FFP needs to be given in a dose of 15-20 mL/kg and therefore requires a large-volume infusion. PCC contains high levels of vitamin K-dependent cofactors and thus involves a smaller-volume infusion than FFP and more rapid administration.[42, 43] However, PCC is associated with high rates of thrombotic complications.
No randomized, controlled trial has studied the safety and efficacy of FFP versus PCC for reversing the effects of warfarin in patients with intracranial hemorrhage. The International Normalised ratio normalisation in patients with Coumarin-related intracranial Haemorrhages (INCH) trial, a prospective, randomized, controlled, multicenter trial comparing the 2 agents, began recruiting subjects in 2009.[44]
FVIIa
Based upon the available medical evidence, the use of FVIIa is currently not recommended over other agents. The PCC available in the United States contains only low levels of FVII, however, and Sarode et al have described successful, rapid reversal of vitamin K antagonist–related coagulopathy using a combination of low-dose FVIIa with PCC, although they note the need for caution in patients at high risk for thrombosis.[41]
Patients on heparin (either unfractionated or low molecular weight heparin [LMWH]) who develop a hemorrhagic stroke should immediately have anticoagulation reversed with protamine.[3] The dose of protamine is dependent upon the dose of heparin that was given and the time elapsed since that dose.
Patients with severe deficiency of a specific coagulation factor who develop spontaneous intracerebral hemorrhage should receive factor replacement therapy.[1]
Reversal of antiplatelet therapy and platelet dysfunction
There is controversy about whether patients on antiplatelet medications (eg, aspirin, aspirin/dipyridamole [Aggrenox], clopidogrel) should be given desmopressin (DDAVP) and/or platelet transfusions. Patients with renal failure and platelet dysfunction may also benefit from the administration of desmopressin (DDAVP). The 2010 AHA/ASA guideline for management of spontaneous intracerebral hemorrhage recommends platelet transfusions only when such hemorrhaging complicates severe thrombocytopenia.[1]
Statins
Inpatient statin use and maintenance may improve outcomes post intracerebral hemorrhage.
In a retrospective multicenter cohort study of 3481 patients with intracerebral hemorrhage over a 10-year period, Flint et al found that inpatients who received a statin (lovastatin, simvastatin, atorvastatin, pravastatin sodium) had better 30-day survival rates following the bleeding event and were more likely to be discharged home or to a rehabilitation center than those who didn’t receive a statin while hospitalized—despite the fact that the statin users had significantly more severe illness and more comorbidities than non statin users.[45, 46] Moreover, those whose statins were discontinued during their hospitalization had worse outcomes than those who remained on statins.
Inpatients treated with a statin had an 18.4% unadjusted 30-day mortality rate compared to 38.7% for those not treated with a statin during their admission.[45, 46] After adjustment for various factors (age, sex, race/ethnicity, comorbidities, number of intracerebral hemorrhage cases by hospital, dysphagia), statin users were also more likely to be alive at 30 days (odds ratio [OR], 4.25; 95% confidence interval [CI], 3.46-5.23; P< .001). Inpatients treated with statins had a 51.1% rate of discharge to home or to a rehabilitation facility compared to 35.0% for patients not treated with statins while hospitalized. Furthermore, patients who discontinued statin therapy after hospital admission had an unadjusted mortality rate of 57.8% compared to 18.9% for patients using a statin before and during hospitalization; they were also significantly less likely to be alive at 30 days (OR, 0.16; 95% CI, 0.12-0.21; P< .001).[45, 46]
Invasive Therapy
A potential treatment for hemorrhagic stroke is surgical evacuation of the hematoma. However, the role of surgical treatment for supratentorial intracranial hemorrhage remains controversial. Outcomes in published studies are conflicting. The international multicenter Trial in Intracerebral Haemorrhage (STICH), which compared early surgery with initial conservative treatment, failed to demonstrate a surgery-related benefit.[47]
In contrast, a meta-analysis of trials for surgical treatment of spontaneous supratentorial intracerebral hemorrhage found evidence for improved outcome with surgery if any of the following applied[48] :
• Surgery undertaken within 8 hours of ictus
• Volume of the hematoma 20-50 mL
• Glasgow coma score 9-12
• Patient age 50-69 years
In addition, evidence suggests that a subset of patients with lobar hematoma but no intraventricular hemorrhage may benefit from intervention.[49] A study in this group of patients (STICH II) has been completed, but results are still pending.[50]
In patients with cerebellar hemorrhage, surgical intervention has been shown to improve outcome if the hematoma is greater than 3 cm in diameter. It can be lifesaving in the prevention of brainstem compression.
Endovascular treatment of aneurysms
Endovascular therapy using coil embolization, as an alternative to surgical clipping, has been increasingly employed in recent years with great success (see the following images), although controversy still exists over which treatment is ultimately superior.
A cerebral angiogram was performed in a 57-year-ol A cerebral angiogram was performed in a 57-year-old man with a family history of subarachnoid hemorrhage and who was found on previous imaging to have a left distal internal carotid artery (ICA) aneurysm. The lateral projection from this angiogram demonstrates a narrow-necked aneurysm arising off the posterior aspect of the distal supraclinoid left ICA, with an additional nipplelike projection off the inferior aspect of the dome of the aneurysm. There is also a mild, lobulated dilatation of the cavernous left ICA.
Follow-up cerebral angiogram after coil embolizati Follow-up cerebral angiogram after coil embolization in a 57-year-old man with a left distal internal carotid artery aneurysm. Multiple coils were placed with sequential occlusion of the aneurysm, including the nipple at its inferior aspect. A small amount of residual filling is noted at the proximal neck of the aneurysm, which may thrombose over time.
The International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling reported that independent survival was higher at 1 year with endovascular coiling and that the survival benefit continued for at least 7 years.[51] This randomized, multicenter, international trial included 2143 patients. The investigators also noted that the risk of late rebleeding was small in both groups but higher in the endovascular coiling group, reconfirming the higher long-term anatomic cure rate of surgery.[51, 52]
More recently, the Barrow Ruptured Aneurysm Trial (BRAT), which included 358 patients, demonstrated superior functional outcome at 1 year with endovascular coil embolization than with microsurgical clipping for acutely ruptured intracerebral aneurysm. Further, in contrast to the ISAT results, no patient in the endovascular embolization group suffered a recurrent hemorrhage.[53] Outcomes at 3-year follow-up of the BRAT patients continued to favor coil embolization, though the difference no longer reached statistical significance.[54]
Endovascular treatment of aneurysms may be favored over surgical clipping under the following circumstances[55] :
• The aneurysm is in a location that is difficult to access surgically, such as the cavernous internal carotid artery (ICA) or the basilar terminus
• The aneurysm is small-necked and located in the posterior fossa
• The patient is elderly
• The patient has a poor clinical grade
The following factors militate against endovascular treatment:
• Wide-based aneurysms or those without an identifiable neck
• Aneurysms with a vessel extending off the aneurysm dome
• Severely atherosclerotic or tortuous vessels that limit the endovascular approach
Although vasospasm may be treated with intra-arterial pharmaceutical agents, such as verapamil or nicardipine, balloon angioplasty can be used for opening larger vessels (see the images below). The combination of the 2 treatments appears to provide safe and long-lasting therapy for severe, clinically significant vasospasm.[56]
Frontal view from a cerebral angiogram in a 41-yea Frontal view from a cerebral angiogram in a 41-year-man who presented 7 days earlier with subarachnoid hemorrhage from a ruptured anterior communicating artery (ACA) aneurysm (which was treated with surgical clipping). There is significant narrowing of the proximal left ACA, left M1 segment, and left supraclinoid internal carotid artery, indicating vasospasm.
Angiographic view in a 41-year-man who presented 7 Angiographic view in a 41-year-man who presented 7 days earlier with subarachnoid hemorrhage from a ruptured anterior communicating artery (ACA) aneurysm (which was treated with surgical clipping). Superimposed road map image demonstrates placement of a wire across the left M1 segment and balloon angioplasty. The left proximal ACA and supraclinoid internal carotid artery (ICA) were also angioplastied, and intra-arterial verapamil was administered. Follow-up image on the right after treatment demonstrates resolution of the left M1 segment and distal ICA, which are now widely patent. Residual narrowing is seen in the left proximal ACA.
Ventriculostomy
Placement of an intraventricular catheter for cerebrospinal fluid drainage (ie, ventriculostomy) is often used in the setting of obstructive hydrocephalus, which is a common complication of thalamic hemorrhage with third-ventricle compression and of cerebellar hemorrhage with fourth-ventricle compression. Ventriculostomies are associated with a risk of infection, including bacterial meningitis.
Prevention of Hemorrhagic Stroke
Antihypertensives
The 2010 AHA/ASA guidelines for spontaneous ICH recommend that after acute intracerebral hemorrhage, patients without medical contraindications should have BP well controlled, especially for hemorrhage in typical hypertensive vasculopathy locations.[1] In addition, the guidelines strongly recommend maintenance of BP below 140/90 mm Hg to prevent a first stroke. In patients with hypertension plus either diabetes or renal disease, the treatment goal is BP below 130/80 mm Hg.[57]
BP-lowering medications include thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs). For patients with diabetes, the use of ACEIs and ARBs to treat hypertension is a class I-A recommendation (strongest and best-documented), according to the 2011 AHA/ASA primary prevention guidelines.[1] Beta blockers are considered second-line agents given their inferiority in preventing vascular events, despite producing similar reductions in BP. (Adverse effects of ACEIs include cough [10%], which is less common with ARBs.)
Although statin therapy is recommended for primary prevention of ischemic stroke (class I-A recommendation),[57] especially if other risk factors are present, some studies have found an increased risk of intracerebral hemorrhage with statin use. However, a meta-analysis of 31 randomized, controlled trials of statin therapy found that active statin therapy was not associated with a significant increase in intracerebral hemorrhage.[58]
In the Heart Outcomes Prevention Evaluation (HOPE) study, the addition of the ACEI ramipril to all other medical therapy, including antiplatelet agents, reduced the relative risk of stroke, death, and myocardial infarction by 32% compared with placebo.[59] Only 40% of the efficacy of ramipril could be attributed to its BP-lowering effects. Other postulated mechanisms included endothelial protection.
Whether the beneficial effect of ramipril represents a class effect of ACEIs or whether it is a property unique to ramipril is unclear.
In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), a regimen based on perindopril, an ACEI, was superior to placebo.[60] Although this drug alone was not superior to placebo, the combination of perindopril with indapamide (a thiazide diuretic) substantially reduced the recurrence of stroke.[60] Much of the effect in reducing stroke recurrence was attributable to the lowering of BP, in contrast to findings for ramipril from the HOPE study.
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) showed slight superiority of chlorthalidone (a thiazide diuretic) over lisinopril (an ACEI) in terms of stroke occurrence.[61]
The Losartan Intervention for Endpoint Reduction in Hypertension Study (LIFE) demonstrated that an ARB (losartan) was superior to a beta blocker (atenolol) in reducing the occurrence of stroke.[62]
The Morbidity and Mortality after Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention (MOSES) study found that the ARB eprosartan was superior to the calcium channel blocker nitrendipine in the secondary prevention of stroke and transient ischemic attack (TIA).[63] This was true despite comparable BP reductions. The absolute annual difference in stroke and TIA risk was approximately 4%. The study was relatively small, and most events were TIAs.
Lifestyle interventions
Smoking cessation, a low-fat diet (eg, Dietary Approaches to Stop Hypertension [DASH] or Mediterranean diets), weight loss, and regular exercise should be encouraged as strongly as pharmacologic treatment. Written prescriptions for exercise and medications for smoking cessation (ie, nicotine patch, bupropion, varenicline) increase the likelihood of success with these interventions.
Reducing sodium intake and increasing consumption of foods high in potassium to reduce BP may also help in primary prevention.[57] High alcohol intake should be reduced, as drinking more than 30 drinks per month has been tied to increased risk of intracerebral hemorrhage.
Exercise
A Finnish study showed that the likelihood of stroke in men with the lowest degree of physical fitness (maximal oxygen uptake [VO2max] < 25.2 mL/kg/min) was more than 3 times greater than in men with the highest degree of physical fitness (VO2max >35.3 mL/kg/min).[64] level of physical fitness was a more powerful risk factor than low-density lipoprotein cholesterol level, body mass index, and smoking, and it was nearly comparable to hypertension as a risk factor.
The 2011 AHA/ASA guidelines for the primary prevention of stroke, which address hemorrhagic and ischemic stroke, emphasize exercise and other lifestyle modifications. The guidelines endorse the 2008 Physical Activity Guidelines for Americans, which include a recommendation of at least 150 minutes per week of moderate-intensity aerobic physical activity.[57]
Consultations
Emergent neurosurgical or neurologic consultation is often indicated; local referral patterns may vary. The need for invasive intracranial pressure monitoring and for emergent cerebral angiography should be assessed by the neurosurgeon. Patients in whom the hemorrhage’s cause is unclear and who would otherwise be candidates for surgery should be considered for angiographic evaluation. Also see Stroke Team Creation and Primary Stroke Center Certification.
Medication
Medication Summary
Medications used in the treatment of acute stroke include anticonvulsants such as diazepam, to prevent seizure recurrence; antihypertensive agents such as labetalol, to reduce blood pressure (BP) and other risk factors for heart disease; and osmotic diuretics such as mannitol, to decrease intracranial pressure in the subarachnoid space.
As previously mentioned, the treatment and management of patients with acute intracerebral hemorrhage depends on the cause and severity of the bleeding. However, there is currently no effective targeted therapy for hemorrhagic stroke.
Anticonvulsants, Other
Class Summary
Benzodiazepines are commonly used to control seizure activity and recurrence. Agents such as lorazepam and diazepam are often used acutely, in combination with either phenytoin or fosphenytoin loading.
Diazepam (Diastat, Diazemuls, Valium)
Diazepam controls active seizures by modulating the postsynaptic effects of gamma-aminobutyric acid type A (GABA-A) transmission, resulting in an increase in presynaptic inhibition. It appears to act on part of the limbic system, the thalamus, and hypothalamus, to induce a calming effect. It also acts as an effective adjunct for the relief of skeletal muscle spasm caused by upper motor neuron disorders.
Diazepam should be augmented by longer-acting anticonvulsants, such as phenytoin or phenobarbital, because it rapidly distributes to other body fat stores.
Lorazepam (Ativan)
Lorazepam is a short-acting acting benzodiazepine with a moderately long half-life. It has become the drug of choice in many centers for treating active seizures.
Anticonvulsants, Hydantoins
Class Summary
Anticonvulsants prevent seizure recurrence and terminate clinical and electrical seizure activity. These agents are used routinely to avoid seizures that may be induced by cortical damage.
According to the American Heart Association/American Stroke Association (AHA/ASA) 2010 guidelines for management of spontaneous intracranial hemorrhage, treatment with antiepileptic drugs is indicated for those patients with clinical seizures or with electroencephalographic (EEG) seizure activity accompanied by a change in mental status.[1] Prophylactic use of anticonvulsants is controversial and should be used judiciously, if at all.
Phenytoin (Dilantin)
Phenytoin may act in the motor cortex, where it may inhibit spread of seizure activity, as well as in the brainstem centers responsible for the tonic phase of grand mal seizures. All doses should be individualized. The antiepileptic effect of phenytoin is not immediate. Concomitant administration of an intravenous benzodiazepine will usually be necessary to control status epilepticus. In addition, a larger dose before retiring should be administered if the dose cannot be divided equally.
Fosphenytoin (Cerebyx)
Fosphenytoin is a diphosphate ester salt of phenytoin that acts as water-soluble prodrug of phenytoin. Phenytoin, in turn, stabilizes neuronal membranes and decreases seizure activity.
To avoid the need to perform molecular-weight-based adjustments when converting between fosphenytoin and phenytoin sodium doses, express the dose as phenytoin sodium equivalents. Although fosphenytoin can be administered intravenously or intramuscularly, the intravenous route is the route of choice and should be used in emergency situations.
The antiepileptic effect of phenytoin, whether given as fosphenytoin or parenteral phenytoin, is not immediate. Concomitant administration of an intravenous benzodiazepine will usually be necessary to control status epilepticus.
Beta Blockers, Alpha Activity
Class Summary
Beta blockers are used to reduce BP and risk factors for heart disease. They are first-line agents for acute BP reduction in hemorrhagic stroke, but they are second-line agents for stroke prevention. Selective beta blockers obstruct access to beta-1 receptors more than they do to beta-2 receptors; nonselective beta blockers obstruct access to beta-1 and beta-2 receptors.
Labetalol (Trandate)
Labetalol blocks beta1-, alpha-, and beta2-adrenergic receptor sites to decrease BP. It is administered as a 5-20 mg intravenous bolus over 2 minutes, then as a continuous infusion at 2 mg/min (not to exceed 300 mg/dose).
Beta Blockers, Beta-1 Selective
Class Summary
Beta blockers are used to reduce BP and risk factors for heart disease. They are first-line agents for acute BP reduction in hemorrhagic stroke, but they are second-line agents for stroke prevention. Selective beta blockers obstruct access to beta-1 receptors more than they do to beta-2 receptors; nonselective beta blockers obstruct access to beta-1 and beta-2 receptors.
Esmolol (Brevibloc)
Esmolol is an ultra-short-acting agent that selectively blocks beta-1 receptors with little or no effect on beta-2 receptor types. This drug is particularly useful in patients with elevated arterial pressure, especially if surgery is planned, and its short half-life of 8 minutes allows for titration and quick discontinuation, if necessary.
Esmolol is also useful in patients at risk for experiencing complications from beta blockade, particularly those with reactive airway disease, mild to moderate left-ventricular dysfunction, and/or peripheral vascular disease.
Vasodilators
Class Summary
Vasodilators lower BP through direct vasodilation and relaxation of the vascular smooth muscle. They are used more for BP lowering in refractory situations.
Hydralazine (Apresoline)
Hydralazine decreases systemic resistance through direct vasodilation of arterioles and is used to treat hypertensive emergencies. The use of a vasodilator will reduce the stroke volume ratio (SVR), which, in turn, may allow forward flow, improving cardiac output. Hydralazine is typically not a first-line agent, because of its side-effect profile.
Calcium Channel Blockers
Class Summary
Calcium channel blockers are used to lower BP by relaxing the blood vessels and increasing the amount of blood and oxygen that is delivered to the heart, while reducing the heart’s workload. In acute situations, intravenous calcium channel blockers are frequently used to control BP. These are first-line agents for long-term BP control in stroke patients (along with thiazides, ACEIs, and angiotensin receptor blockers [ARBs]).
Nicardipine (Cardene, Cardene IV, Cardene SR)
Nicardipine relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery and reduces myocardial oxygen consumption.
Angiotensin-converting Enzyme Inhibitors
Class Summary
ACEIs prevent the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion. These are first-line agents for emergent and long-term BP control in hemorrhagic stroke patients.
Enalapril (Vasotec)
Enalapril prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion. It helps to control BP and proteinuria.
Ramipril (Altace)
Ramipril prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.
Lisinopril (Zestril)
Lisinopril prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.
Angiotensin Receptor Blockers
Class Summary
ARBs may be used as an alternative to ACEIs in patients who develop adverse effects, such as a persistent cough.
Losartan (Cozaar)
Losartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. It may induce a more complete inhibition of the renin-angiotensin system than ACEIs do. In addition, it does not affect the response to bradykinin and is less likely to be associated with cough and angioedema.
Candesartan (Atacand)
Candesartan blocks vasoconstriction and the aldosterone-secreting effects of angiotensin II. It may induce a more complete inhibition of the renin-angiotensin system than ACEIs do. In addition, it does not affect response to bradykinin and is less likely to be associated with cough and angioedema.
Valsartan (Diovan)
Valsartan produces direct antagonism of angiotensin II receptors. It displaces angiotensin II from the AT1 receptor and may lower BP by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses.
Diuretics, Thiazide
Class Summary
Thiazide diuretics inhibit sodium and chloride reabsorption in the distal tubules of the kidney, resulting in increased urinary excretion of sodium and water.
Hydrochlorothiazide (Microzide)
Hydrochlorothiazide inhibits the reabsorption of sodium in distal tubules, causing increased excretion of sodium and water, as well as potassium and hydrogen ions.
Chlorthalidone (Diuril)
Chlorthalidone inhibits the reabsorption of sodium in distal tubules, causing increased excretion of sodium and water, as well as potassium and hydrogen ions.
Diuretics, Osmotic Agents
Class Summary
Osmotic diuretics, such as mannitol, may be used to decrease intracranial pressure in the subarachnoid space. As water diffuses from the subarachnoid space into the intravascular compartment, pressure in the subarachnoid compartment may decrease.
Mannitol (Osmitrol)
Mannitol reduces cerebral edema with the help of osmotic forces. It also decreases blood viscosity, resulting in reflex vasoconstriction and lowering of intracranial pressure.
Analgesics, Other
Class Summary
Because hyperthermia may exacerbate neurologic injury, these agents may be given to reduce fever and relieve pain.
Acetaminophen (Tylenol, FeverAll, Aspirin Free Anacin)
Acetaminophen reduces fever, maintains normothermia, and reduces headache.
Hemostatics
Class Summary
Vitamin K is used to promote the formation of clotting factors. Phytonadione can overcome the competitive block produced by warfarin and other related anticoagulants. A fresh frozen plasma (FFP) infusion followed by oral vitamin K should be given without delay in the emergency department to manage warfarin-related intracranial hemorrhage.
Vitamin K1 (phytonadione; vitamin K, Mephyton, AquaMephyton)
Phytonadione can overcome the competitive block produced by warfarin and other related anticoagulants. Vitamin K3 (menadione) is not effective for this purpose. There is a delay of the clinical effect for several hours while liver synthesis of the clotting factors is initiated and plasma levels of clotting factors II, VII, IX, and X are gradually restored.
Phytonadione should not be administered prophylactically and is used only if evidence of anticoagulation exists. The required dose varies with the clinical situation, including the dose and duration of action of the anticoagulant ingested. Intravenous phytonadione is recommended for life-threatening bleeding, including intracerebral hemorrhage complicating warfarin therapy, although it carries a small risk of anaphylaxis.
Blood Components
Class Summary
These agents are indicated for the correction of abnormal hemostatic parameters.
Fresh frozen plasma
Plasma, the fluid component of blood, contains the blood's soluble clotting factors. FFP is created by separating plasma from a unit of blood and freezing it for use in patients with blood-product deficiencies.
Platelets
Platelets are fragments of large bone marrow cells found in the blood that play a role in blood coagulation. A single random donor unit of platelets per 10 kg is administered in adults when the platelet count drops below 50,000/µL.
Prothrombin complex concentrate (Bebulin VH, Profilnine SD)
Prothrombin complex concentrate (PCC) is a mixture of vitamin K-dependent clotting factors found in normal plasma that replaces deficient clotting factors, provides an increase in plasma levels of factor IX, and can temporarily correct a coagulation defect in patients with factor IX deficiency. PCC is usually reserved for situations in which volume overload is a concern.
Antidotes, Other
Class Summary
Protamine is used to neutralize the effects of anticoagulants.
Protamine
Protamine sulfate forms a salt with heparin and neutralizes its effects. The dosage administered is dependent on the amount of time that has passed since heparin was given.
Vasopressin-Related
Class Summary
These agents improve bleeding time and hemostasis.
Desmopressin acetate (DDAVP, Stimate)
Desmopressin releases von Willebrand protein from endothelial cells. It improves bleeding time and hemostasis in patients with mild and moderate von Willebrand disease without abnormal molecular forms of von Willebrand protein. It is effective in uremic bleeding. Tachyphylaxis usually develops after 48 hours, but the drug can be effective again after several days.
Questions & Answers
Overview
What is hemorrhagic stroke?
What are the signs and symptoms of hemorrhagic stroke?
What are deficits of hemorrhagic stroke characteristic of involvement of the left hemisphere of the brain?
What are deficits of hemorrhagic stroke characteristic of involvement of the right hemisphere of the brain?
Which lab tests are performed in the evaluation of hemorrhagic stroke?
What is the role of brain imaging in the evaluation of suspected hemorrhagic stroke?
What is included in the treatment of acute hemorrhagic stroke?
What is the role of surgery in the management of hemorrhagic stroke?
What is the role of endovascular therapy for the treatment of hemorrhagic stroke?
What is hemorrhagic stroke?
What are the clinical presentations of hemorrhagic stroke?
When is brain imaging performed in the evaluation of hemorrhagic stroke?
What anatomy is useful for the understanding of hemorrhagic stroke?
What is the anatomy of the brain involved in hemorrhagic stroke?
What is the pathophysiology of hemorrhagic stroke?
What is the role of subarachnoid hemorrhage (SAH) in the pathogenesis of hemorrhagic stroke?
How are the etiologies of hemorrhagic stroke categorized?
Which factors increase the risk of hemorrhagic stroke?
What are the causes of hemorrhagic stroke?
What is the most common etiology of primary hemorrhagic stroke?
What is the role of amyloidosis in the etiology of hemorrhagic stroke?
What is the role of coagulopathy in the etiology of hemorrhagic stroke?
What is the role of anticoagulant therapy in the etiology of hemorrhagic stroke?
What is the role of arteriovenous malformations in the etiology of hemorrhagic stroke?
What is the role of aneurysm in the etiology of hemorrhagic stroke?
What are common sites of aneurysms associated with hemorrhagic stroke?
What is the role of genetics in the etiology of hemorrhagic stroke?
What is Loeys-Dietz syndrome (LDS)?
What is the role of Ehlers-Danlos syndrome in the etiology of hemorrhagic stroke?
Where can information on genetics and hemorrhagic stroke be found?
What is the role of hemorrhagic transformation in the etiology of stroke?
What is the incidence of hemorrhagic stroke in the US?
What are the demographic variations in the prevalence of hemorrhagic stroke in the US?
What is the global incidence of hemorrhagic stroke?
What are the racial predilections of hemorrhagic stroke?
What is the prognosis of hemorrhagic stroke?
What is the intracerebral hemorrhage score and how is it calculated for hemorrhagic stroke?
How are the intracerebral hemorrhage scores for the prognosis of hemorrhagic stroke interpreted?
What are prognostic factors for hemorrhagic stroke?
How should Do Not Resuscitate (DNR) orders be handled in patients with hemorrhagic stroke?
Presentation
What is the focus of medical history in patients with hemorrhagic stroke?
What are hemorrhagic and ischemic stroke differentiated?
What are focal symptoms of hemorrhagic stroke?
What are symptoms of subarachnoid hemorrhage (SAH) in hemorrhagic stroke?
What are the most common clinical scoring systems for grading aneurysmal subarachnoid hemorrhage (SAH) in hemorrhagic stroke?
What is included in the assessment of suspected hemorrhagic stroke?
What are physical findings characteristic of hemorrhagic stroke?
How are physical exam results quantified for hemorrhagic stroke?
Which neurologic deficits are associated with hemorrhagic stroke in the left brain hemisphere?
Which neurologic deficits are associated with hemorrhagic stroke in the right brain hemisphere?
What can result from nondominant hemisphere syndrome in hemorrhagic stroke?
What are the indications of cerebellum involvement in hemorrhagic stroke?
What are the specific brain site deficits of hemorrhagic stroke?
What are signs of cerebellar or brainstem involvement in hemorrhagic stroke?
DDX
How is hemorrhagic stroke differentiated from ischemic stroke?
What are the differential diagnoses for Hemorrhagic Stroke?
Workup
What is the role of lab testing in the diagnosis of hemorrhagic stroke?
What is the role of brain imaging in the evaluation of hemorrhagic stroke?
What is the role of CT scanning in the diagnosis of hemorrhagic stroke?
When is CT angiography and contrast-enhanced CT indicated in the workup of hemorrhagic stroke?
What is the role of angiography in the diagnosis of hemorrhagic stroke?
What is the role of MRA in the evaluation of hemorrhagic stroke?
Treatment
What is included in the treatment of acute hemorrhagic stroke depend on?
What is the initial management of hemorrhagic stroke?
What is effective targeted therapy for hemorrhagic stroke?
How does intensive blood pressure reduction affect hematomas in hemorrhagic stroke?
What is the prevalence of seizures in hemorrhagic stroke?
How are seizures treated in hemorrhagic stroke?
What is the role of prophylactic anticonvulsant medication in hemorrhagic stroke?
What are the AHA/ASA guidelines for the use of prophylactic anticonvulsant medication in the treatment of hemorrhagic stroke?
What is optimal blood pressure (BP) control in hemorrhagic stroke?
What is the role of blood pressure (BP) reduction in the treatment of hemorrhagic stroke?
Which medications are useful to reduce blood pressure (BP) in the treatment of hemorrhagic stroke?
What are the AHA/ASA guidelines for treating elevated blood pressure (BP) in hemorrhagic stroke?
What are the AHA/ASA guidelines for BP management in patients with aneurysmal subarachnoid hemorrhage (SAH)?
What are the ACP/AAFP treatment guidelines for persistent systolic blood pressure (BP) in the prevention of hemorrhagic stroke?
What is the cause of elevated intracranial pressure in hemorrhagic stroke?
What are the options for intracranial pressure control in hemorrhagic stroke?
What is the role of hemostatic therapy for hemorrhagic stroke?
What is the efficacy of hemostatic therapy in the treatment of hemorrhagic stroke?
How is the risk of hemorrhagic stroke increased in patients on warfarin?
What are the options for warfarin reversal in patients with hemorrhagic stroke?
What is the difference between using fresh frozen plasma (FFP) and prothrombin complex concentrates (PCC) for the treatment of hemorrhagic stroke?
What is the role of recombinant factor VIIa (rFVIIa) in the treatment of hemorrhagic stroke?
What are the treatment options for hemorrhagic stroke caused by platelet dysfunction?
What is the benefit of statin use in the treatment of hemorrhagic stroke?
What is the role of statins in the treatment of hemorrhagic stroke?
When is surgery indicated in the treatment of hemorrhagic stroke?
Which factors improve the outcome of surgery treatment of hemorrhagic stroke?
What is the benefit of surgical intervention in a cerebellar hemorrhagic stroke?
What is the role of endovascular therapy in the treatment of hemorrhagic stroke?
What is the efficacy of endovascular coiling for the treatment of hemorrhagic stroke?
What are the benefits of endovascular coil embolization compared with microsurgical clipping in the treatment of aneurysm in hemorrhagic stroke?
When is endovascular treatment of aneurysms indicated in the treatment of hemorrhagic stroke?
When is endovascular treatment of aneurysms contraindicated in hemorrhagic stroke?
What is the efficacy of combining medication and balloon angioplasty in the treatment of hemorrhagic stroke?
What is the role of ventriculostomy in the treatment of hemorrhagic stroke?
What are the AHA/ASA treatment guidelines for spontaneous intracranial hemorrhage (ICH) in hemorrhagic stroke?
Which medications are used to lower blood pressure (BP)-in the treatment of hemorrhagic stroke?
What are possible adverse effects of statin therapy in the treatment of hemorrhagic stroke?
What is the role of antiplatelet therapy in the prevention of hemorrhagic stroke?
What is the role of perindopril in the prevention of hemorrhagic stroke?
How does chlorthalidone compare to lisinopril for the prevention of hemorrhagic stroke?
How does losartan compare to atenolol for the prevention of hemorrhagic stroke?
How does nitrendipine compare to eprosartan for the prevention of hemorrhagic stroke?
What are the lifestyle interventions for prevention of hemorrhagic stroke?
What is the role of exercise in the prevention of hemorrhagic stroke?
Which specialist consultation are needed for the management of hemorrhagic stroke?
Medications
Which medications are used in the treatment of hemorrhagic stroke?
What factors determine the treatment approach for hemorrhagic stroke?
Which medications in the drug class Vasopressin-Related are used in the treatment of Hemorrhagic Stroke?
Which medications in the drug class Antidotes, Other are used in the treatment of Hemorrhagic Stroke?
Which medications in the drug class Blood Components are used in the treatment of Hemorrhagic Stroke?
Which medications in the drug class Hemostatics are used in the treatment of Hemorrhagic Stroke?
Which medications in the drug class Analgesics, Other are used in the treatment of Hemorrhagic Stroke?
Which medications in the drug class Diuretics, Osmotic Agents are used in the treatment of Hemorrhagic Stroke?
Which medications in the drug class Diuretics, Thiazide are used in the treatment of Hemorrhagic Stroke?
Which medications in the drug class Angiotensin Receptor Blockers are used in the treatment of Hemorrhagic Stroke?
Which medications in the drug class Angiotensin-converting Enzyme Inhibitors are used in the treatment of Hemorrhagic Stroke?
Which medications in the drug class Calcium Channel Blockers are used in the treatment of Hemorrhagic Stroke?
Which medications in the drug class Vasodilators are used in the treatment of Hemorrhagic Stroke?
Which medications in the drug class Beta Blockers, Beta-1 Selective are used in the treatment of Hemorrhagic Stroke?
Which medications in the drug class Beta Blockers, Alpha Activity are used in the treatment of Hemorrhagic Stroke?
Which medications in the drug class Anticonvulsants, Hydantoins are used in the treatment of Hemorrhagic Stroke?
Which medications in the drug class Anticonvulsants, Other are used in the treatment of Hemorrhagic Stroke?
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79,987,759,700,354,320 | Why Does Lung Cancer Cause Weight Loss?
Please share this one!
Weight loss is quite common in people with lung cancer. Even sometime it can be one of the early symptoms of the disease, though many times this cancer doesn’t cause early signs and symptoms. And there are several reasons of why lung cancer can cause weight loss.
Weight loss is common in many cancers
Unintended weight loss can be abnormal, especially if it occurs without known cause. Unfortunately, it’s not always easy to find the underlying cause of the problem.
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image_illustration389In fact, it s also attributed by lots of factors! There are many conditions that can contribute to cause weight loss. In other words, it can be a symptom of numerous different conditions – and one of them could be cancer.
However, in some cases it is caused by minor condition that even may improve without treatment. But in general, you should see a doctor promptly if you lose more than 10 pounds without trying!
Weight loss problem can be found in about 40 percent of patients with cancer. Even for those with advanced cancer, most of them have it.
In cancer, it usually occurs together with other similar symptoms such as lack of energy (fatigue), weakness, and difficulty in daily activities. Though it is very common in cancer, but this may be not fully understood yet.
However, some theories have been proposed. If you have cancer, your cancer may use up much of energy, and as a result you can be easier to have lack of energy.
At the same time, you have loss of appetite. You tend eat less than usual and cannot replace the energy that you have lost. These result in abnormal weight loss!
Why does lung cancer cause weight loss?
When the cancer is still too small and completely in the lung (it doesn’t spread yet), lung cancer is less likely to cause symptom including weight loss.
As the cancer grows, it will be more intense in affecting the lung function or other parts of the body. For more information about the symptoms of lung cancer, see this section!
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In a few cases, early cancer in the lung may have caused some early symptoms and one of them could be weight loss. For such cases, patients are more likely to seek help and lung cancer may be caught early.
Weight loss in people with lung cancer can occur in a number of different ways.
The following are some helpful explanations!
The high demand on using the energy
In essence, weight loss related to cancer occurs because the demand of using energy increases significantly but you cannot replace the energy that you have lost!
Theoretically, you will lose weight if the calorie or energy that you eat from food is lower than what you burn (use). And if you have cancer, your body works harder to fight against the cancer. The cancer itself may also use up of much energy to grow and develop, as noted before.
These can cause a significant increase in the demand of using your energy. And at the same time, it’s always not easy to eat as well for people with cancer. For instance, decreased appetite or even appetite loss is a common symptom in lung cancer.
Appetite loss
Your appetite plays a key role in your diet. If you have poor appetite, you can find foods unappealing and you are likely to eat less. And as a result, weight loss occurs.
In lung cancer, appetite problem can be attributed by a number of different things, from cancer itself to the cancer treatments.
For instance, there is a chance for the cancer to affect your metabolism. And this may contribute to decrease your appetite. Pain in lung cancer is also common, and this symptom may also affect your appetite.
Furthermore, other side effects of some treatments for cancer may also contribute to affect your appetite.
Your shortness of breath may also have an effect on your weight
As well we know that breathless or shortness of breath is very common in patients with lung cancer. Even it is one of the most common symptoms.
The cancer grows in the lung and it can affect many functions of the lung. Even if necessary, one lung can be completely removed with surgery in order to remove the cancer tumor. And breathing with one lung is more difficult!
All of these can cause difficulty breathing. You can use more energy just for breathing.
Normally, you only need about 100 calories per day to use your lung for breathing. These calories are required to expand and contract the muscles involved in breathing. But this number can increase quite high if you have lung cancer. This extra work can slightly contribute to cause weight loss, too.
Metastasis of lung cancer
Why is weight loss more common in advanced stages?
When the cancer has become advanced, more energy required by the body to fight against the cancer. Advanced stages means there are more areas of the body affected by the cancer, and this can drain your energy more!
Metastasis of lung cancer can be another answer. For instances:
.
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7,599,066,802,309,663,000 | Defining epileptogenic networks: Contribution of SEEG and signal analysis
Summary
Epileptogenic networks are defined by the brain regions involved in the production and propagation of epileptic activities. In this review we describe the historical, methodologic, and conceptual bases of this model in the analysis of electrophysiologic intracerebral recordings. In the context of epilepsy surgery, the determination of cerebral regions producing seizures (i.e., the “epileptogenic zone”) is a crucial objective. In contrast with a traditional focal vision of focal drug-resistant epilepsies, the concept of epileptogenic networks has been progressively introduced as a model better able to describe the complexity of seizure dynamics and realistically describe the distribution of epileptogenic anomalies in the brain. The concept of epileptogenic networks is historically linked to the development of the stereoelectroencephalography (SEEG) method and subsequent introduction of means of quantifying the recorded signals. Seizures, and preictal and interictal discharges produce clear patterns on SEEG. These patterns can be analyzed utilizing signal analysis methods that quantify high-frequency oscillations or changes in functional connectivity. Dramatic changes in SEEG brain connectivity can be described during seizure genesis and propagation within cortical and subcortical regions, associated with the production of different patterns of seizure semiology. The interictal state is characterized by networks generating abnormal activities (interictal spikes) and also by modified functional properties. The introduction of novel approaches to large-scale modeling of these networks offers new methods in the goal of better predicting the effects of epilepsy surgery. The epileptogenic network concept is a key factor in identifying the anatomic distribution of the epileptogenic process, which is particularly important in the context of epilepsy surgery.
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-3,185,781,168,436,079,600 | Pain in Corner of Eye (Outer & Inner): 10 Causes & Solution
Why does the corner of my eye hurt? When should I be concerned about pain in corner of eye? Today’s topic is all about the sore or pain in the outer and inner corners of the eye: Introduction, Causes, Home Remedies, and Treatment. So, stay connected.
Introduction
Most of us have experienced sore outer or inner corner of the eye, either mild or severe, at least once in a while.
Pain in the eye can be felt in several different areas, such as eyeball, eye surface, eye socket, eyelid margin, or outer and inner eye corners.
Between the outer and inner canthi, the eye corner near the nose is more susceptible to pain, along with itching, redness, and swelling.
In order to properly define the type of pain you’re experiencing, doctors first need to pinpoint the specific location of pain, and cause of the eye pain in the corner.
Pain in the corner of the eye can be caused by several factors. In most cases, the pain can be reduced with the help of simple home remedies, while in other cases the eye problem can be successfully treated by your eye doctor.
We’re going to cover a few common causes of pain in the corner of your eye, and what you can do to alleviate the discomfort.
Pain in the corner of the eye can be related to several different factors. Find out what can cause pain in the corner of your eye, as well as when you should see a specialist.
pain-in-corner-of-eye-hurts-outer-inner
Common Causes and Treatment of Pain in Corner of Eye (Outer or Inner)
Most of the factors responsible for eye pain in the outer and inner corners of the eye are similar, while few of them are creating trouble only to the eye corner near to the nose. The potential causes of pain in the corner of your eye are mentioned below with their treatment options.
Pain in Inner Corner of Eye
The corner of the eye near the nose is more susceptible to infection, itchiness, and redness due to the presence of tear ducts, and other eye structures such as caruncle and puncta, as compared to the lateral or outer corner.
In addition, the tear debris collected from the entire anterior eye surface by the tear is first gets accumulated in the inner corner of the eye before being drained down the tear duct. This also increases the likelihood of eye pain and other problems in the inner canthal region.
In general, the following causative factors are responsible for mild to severe eye pain in the inner corner of the eye.
Tear duct infection (dacryocystitis)
The tear duct or nasolacrimal duct is a tiny canal through which the tear is drained down to the nasal cavity. The unobstructed, continuous flow of tear through this duct is vital to maintain a healthy eye surface and to regulate the amount of tear in the eye.
Due to any reason, if the tear duct is clogged, the tear can’t pass down easily resulting in swelling and pain in the inner corner of the eye close to the nose.
The blocked tear duct provides a favorable environment to the bacteria such as Staphylococcus (staph) and Streptococcus (strep) species, which causes the infection of the tear duct or dacryocystitis.
Oral and ocular antibiotics in addition to warm compression and gentle massage treat the mild to moderate condition of dacryocystitis, while surgery is indicated in chronic and repeated cases of dacryocystitis.
Foreign Body
Foreign bodies such as eyelashes, sand, dust, metal, glass, etc., can affect any part of your eye, including the outer and inner corners.
When you have a foreign body inside the eye, you may feel gritty sensation, sensitivity to light (photophobia), pain, redness, and occasional blurry vision.
You can flush your eyes with clean water to easily remove the tiny particles at the superficial surface of the eye.
However, the foreign bodies lodged in the deep surface require medical attention to remove them and to treat the condition effectively.
Trauma or Eye Injury
An injury in and around the eye, especially towards the nasal area leads to pain in the inner corner of the eye.
Eye injury not only hurts the eye corner, but also affects the other parts of the eye, so, injury of any severity should be treated by the eye specialist.
Stye or Hordeolum
A stye is a painful swollen mass or bumps at the edge or other parts of the eyelid. If the bump is seen in the eyelid near the nose or inner eye corner, you will experience pain, burning sensation, excessive tearing, light sensitivity, and a gritty sensation.
Two types of stye are external and internal stye. Both of these conditions are responsible for pain in corner of eye.
Hordeolum or stye often heal on their own within a couple of weeks. To accelerate the healing process, you can apply hot compression to the affected area.
If the painful swollen mass doesn’t heal on its own, visit the eye doctor as the stye might need antibiotics or surgical removal.
Pterygium and Pinguecula
Pinguecula is an asymptomatic, yellowish mass seen on the bulbar conjunctiva. Likewise, pterygium is the vascular, fleshy tissue that grows towards the cornea of the eye. In normal conditions, both of these masses of the conjunctiva do not provide redness and pain to the eye. But the inflamed condition of both of them leads to pain, especially while moving the eyeball.
The inflamed pinguecula and pterygium of the nasal bulbar conjunctiva of the eye make the inner corner of the eye hurt.
Both of these eye conditions do not require treatment, but the inflamed conditions should be treated with non-steroid or steroid eye drops.
Large pterygium encroaching the cornea might block the visual axis of the eye, causing blurred vision. In such cases, surgical excision of the pterygium is mandatory.
Blepharitis
Another main cause of pain in the inner corner of the eye is blepharitis. Angular blepharitis that is caused by a bacterial infection (Moraxellaspecies) not only causes eyelid pain but also causes itching in the eyelid margins and corners.
Maintaining good eyelids hygiene helps to reduce the problem of blepharitis. For this, clean the eyelid skin and margins with warm water or shampoo regularly for two weeks.
Meibomian Gland Dysfunction (MGD)
When the mouth of the oil glands that are present in the tarsal plate or both upper and lower eyelids are blocked, you will notice yellowish pimples at the margin of the eyelids. This eye condition is called meibomian gland dysfunction or MGD.
MGDs present at the eyelids near the inner corner of the eye makes you feel mild to moderate pain, especially when you touch the affected area.
Warm compression helps to open the mouth of the oil glands and solve the problem within several days.
Eye Allergy (Hypersensitivity)
Another potential cause of pain in the inner corner of the eye is eye allergy. Eye allergy or hypersensitivity reaction to any allergen or contact lens leads to eye itching in the corner, in response to which you scratch your eyes, and that might cause pain in the inner corner of the eye along with eyelids.
To solve the problem, the first thing you have to do is to stop scratching your eyes. You can apply cold compression to minimize eye pain.
Likewise, Over-the-counter antihistaminic eye drops help to alleviate the problem. In severe forms of eye allergy, you have to seek medical attention to treat the condition effectively.
You have to discontinue the use of contact lenses until the condition is completely healed.
Eyeglasses
The solution for one problem sometimes might give rise to another problem. The same goes here if the eyeglasses are not fitted properly on your face. The nose pad of the frame will create a depression in the base of the nose bridge or the inner corner of the eye.
A poorly fitted spectacle frame is one of the common causes of pain in the inner corner of the eye.
To solve this problem, always make spectacle with proper measurement from the professionals (optometrists or opticians).
Eye Fatigue
Consistent near work for a prolonged time, especially the computer work or any visual display work, makes your eyes tired and you will feel pain behind the eyeball and the inner corner of the eye.
Eye fatigue and pain in and around the eye are some of the components of computer vision syndrome or digital eye strain.
The problem can be solved by using anti-glare glasses (ARC lenses), taking proper rest in between the working hours (follow 20-20-20 rules), and using over-the-counter lubricating eye drops.
Pain in Outer Corner of Eye: Sore Outer Corner of Eye
Similar to pain in the inner corner of the eye, the sore outer corner of the eye is also the consequence of the above-mentioned causative factors.
The outer canthus or corner of the eye is prone to injury more than the inner or medial canthus as only a small portion of it is protected by the orbit bone. So, injury is the main causative factor of pain in the outer corner of the eye.
Unlike the inner corner of the eye, the outer corner doesn’t possess a tear duct or nasolacrimal duct. That’s why, only the corner of the eye near the nose is affected by any abnormalities in the tear duct, such as infection, or swelling.
Another main cause of pain in the outer corner of the eye is blepharitis. Angular blepharitis that is caused by a bacterial infection (Moraxellaspecies) not only causes eyelid pain but also causes itching in the eyelid margins and corners.
Likewise, stye or hordeolum also leads to pain in the outer corner of the eye, along with swelling and mild itchy sensation of the eyelids.
The outer corner of your eye hurts if there is inflamed pterygium or pinguecula at the lateral bulbar conjunctiva of the eye.
Meibomian gland dysfunction is another causative factor of the sore outer corner of the eye due to the blocked opening of tear-oil glands at the margin of both eyelids.
Similarly, eye allergy or hypersensitivity reaction to any allergen or contact lens leads to eye itching in the corner, in response to which you might scratch your eyes, and that might cause pain in the outer corner of the eye along with eyelids.
Home Remedies
Some of the causative factors that are responsible for pain localized in the corner of the eye can be treated at home, while others require medical treatment.
Maintaining good eyelids hygiene helps to reduce the problem of blepharitis and MGDs. For this, clean the eyelid skin and margins with warm water regularly for two weeks. Similarly, apply warm compression in the affected eyelids and eye corners to minimize the pain caused by stye, hordeolum, or MGDs.
The eyelashes and other foreign bodies inside the eye also cause pain in the eye. Any objects close to the eyelids and surface of the eye can be removed by applying clean water to the eye. In case of pain in the eye corner due to a deep-seated foreign body, you need to visit the eye doctor to remove the object.
If you have an allergic reaction to the eye, the first thing you have to do is to stop rubbing or scratching the eyelids and eye corners. Over-the-counter antihistaminic eye drops help to alleviate the problem. Likewise, you can apply cold (ice) to the affected eye corner that provides a soothing effect and minimize the pain.
Other causes of the sore outer or inner corners of the eye, such as eye injury or infection of the tear duct require medical treatment for successful management of the cause of the eye pain.
When to See a Doctor
Medical attention is necessary in case of eye pain in the corner of the eye that doesn’t go away with home remedies, and if the pain lasts for several days.
If you notice any of the following eye signs and symptoms when the corner of your eye hurts, see your eye doctor.
• If there is unendurable pain in the eye
• Trauma to the eye due to physical injury or chemicals
• If you feel something inside your eye
• Discharge of thick pus, blood, or excessive watering
• If the eye pain in the corner comes with swelling, redness
• Sudden change in vision (blurry vision, double vision)
• Pain in the eye movement
• Difficulty in opening your eyes
Takeaway
Acute pain in the corner of the eye should be taken care of right away because it can develop into a more severe case if it is left untreated. You should try to decrease the chances of further complications by treating them as soon as you can.
In the majority of the cases, pain in corner of eye is not dangerous, just uncomfortable. They can be treated at home by simply applying warm compression, gentle massage, or over-the-counter lubricating eye drops.
But, if your eye hurts in the corner due to tear duct infection, or injury immediate medical attention is necessary. Sudden changes in vision accompanied by eye pain in either the outer or inner corner of the eye is a condition of ocular emergency. In such circumstances, visit your eye doctor to rule out the underlying cause and to start the treatment.
In addition, you should avoid eye cosmetics and contact lenses until the condition is completely healed. Similarly, do not rely on over-the-counter eye drops if the pain in corner of eye lasts for many days.
Sources
• https://www.aao.org/eye-health/diseases/pink-eye-conjunctivitis
• https://www.medicalnewstoday.com/articles/264419
• https://www.healthline.com/health/dry-itchy-eyes
• https://www.healthline.com/health/blepharitis
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"Is the national rise in obesity causing my daughter to become fatter?"
ZocdocAnswersIs the national rise in obesity causing my daughter to become fatter?
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I realize a lot of people are fat in the south, but could watching TV and being around so many fat people cause my daughter to eat more than she should?
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There is a lot of medical, social science, and anthropological evidence that peer and societal influences on an individual's health habits influence their behaviors and outcomes. This is the case for smoking, drug use, but most of all, diet and exercise. As children go forth in school and begin to socialize more in peer groups, their peers start to influence their fitness and nutritional habits. A child with friends who are sedentary and have bad nutritional habits is more likely to have these problems as well. Ultimately, it is important for parents to try to exert an opposite influence on their overweight children's diet and exercise habits. While you want to avoid alienating her from her friends, you should educate her about what the best types of foods are, what foods to avoid, portion sizes, avoiding sugary beverages, exercising regularly, etc. Your daughter's pediatrician can help with this, and may ultimately wish to make a referral to a nutritionist.
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6,282,358,036,187,078,000 | The Thyroid Lifestyle
This article is written as part of a system for creating optimal thyroid function. In some people this is automatic and doesn’t need to be refined. In many of us, we must ‘train’ our body to use thyroid hormone optimally. That requires ideal nutrition, supplementation to baseline or above, optimization of workouts and food intake, sleep, water intake, etc. This is the lifestyle side of the equation.
PEAK HEALTH = LIFESTYLE MEASURES + BIOCHEMISTRY + MOVEMENT/EXERCISE + MENTAL
The morning routine:
This may be the most important part healthy thyroid function, along with sleep.
Wake time:
Pick a time. A time you can wake up everyday at. Ideally in the 5 or 6 o’clock hours. And you must commit yourself to getting up at this time every single day. No questions asked.
Note: if you are taking a thyroid hormone medication or supplement, This will fit right into your routine. You can add this to the same time you wake up at. Keep the body in a rhythm.
Move right away in the morning:
You must get the heart rate up to stimulate the body to get going. Dopamine (we will cover shortly), Cortisol and Thyroid hormones all rise in the morning. I have found when you stimulate all 3 together right away in the morning, all 3 function more smoothly and optimally. Getting up and moving right away in the morning is a great way to increase body temperature (thyroid function) and increase cortisol and get the body in rhythm.
Breakfast:
Depending on if you are taking thyroid supplements or prescription hormones, breakfast time can vary. I am a big fan of eating breakfast in the first 60 min of waking and before drinking coffee. Coffee suppresses hunger, even though it does boost dopamine. Protein is a better dopamine optimizer than coffee, which is why I find it best for thyroid function to eat protein before drinking the coffee.
Food intake during the day:
The thyroid responds to calories. Yes, physiology has always stated carbs support thyroid function, but in clinical practice we have found meal frequency is equal, if not better at improving thyroid function than carbs. Plus, most people with a thyroid problem don’t want to eat carbs when trying to improve their thyroid for obvious reasons.
Sleep:
Must be maximized in order to have proper thyroid function. If you aren’t sleeping well, your thyroid is not working well. It is that simple.
How do you know if you aren’t getting good sleep?
1. Under 7.5 hours of sleep.
2. Snoring. You 100% are not sleeping well if you snore.
3. Tossing and turning during your slumber. This is easy to identify. If you sheets and blankets are torn apart, you are not getting good sleep.
4. Waking up during the night to pee or do other things.
Sleep quality and quantity is necessary to have optimal thyroid function. Your body must fully shut down and revitalize at night in order for the ‘energy’ hormone to optimally turn on and function in the way you want it to.
Begin to incorporate these things into your life and your thyroid function will improve.
Get Optimized!
-Dr. Kurt | {
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-8,567,552,928,402,810,000 | Îñîáåííîñòè ðàáîòû âðà÷à ñòîìàòîëîãà ñòîÿ. Èçìåíåíèÿ ãðóäíîé êëåòêè îò ñòîÿ÷åé ðàáîòû
Ïðè îïèñàíèè ìû áóäåì îñòàíàâëèâàòüñÿ òîëüêî íà ðàáî÷åé ïîçå â ïîâñåäíåâíîé äåÿòåëüíîñòè âðà÷à. Êàê èçâåñòíî, ðàçëè÷àþò ðàáîòó ñòîìàòîëîãà ñòîÿ è ñèäÿ. Áîëüøèíñòâî âðà÷åé è ïî ñåé äåíü, ê ñîæàëåíèþ, ðàáîòàþò ñòîÿ.
Ïðè äëèòåëüíîé ðàáîòå ñòîÿ âûíóæäåííàÿ ïîñòîÿííàÿ ðàáîòà ìûøö íîã è êîðïóñà óæå ñàìà ïî ñåáå ïðèâîäèò ê óñòàëîñòè. Ê òîìó æå âðà÷ íàêëîíÿåòñÿ, åãî ðóêè ðàçâåäåíû, ÷òî äîïîëíèòåëüíî íàãðóæàåò çàòûëî÷íûå è ñïèííûå ìûøöû. Ýòî ïðèâîäèò ê èçìåíåíèþ óñëîâèé êðîâîñíàáæåíèÿ è ðàñïðåäåëåíèÿ êðîâè. Âîçíèêàþò ãîëîâîêðóæåíèÿ, îáìîðîêè, ó æåíùèí óñèëèâàåòñÿ ìåíñòðóàöèÿ, ÷àùå è òÿæåëåå ïðîòåêàþò çàáîëåâàíèÿ íèæíåé ÷àñòè æèâîòà. Ïîÿâëÿþòñÿ æàëîáû íà îùóùåíèÿ ðàçíîãî ðîäà, â îñîáåííîñòè â íîãàõ, â ÷àñòíîñòè íà ñïàçìû ñîñóäîâ.
Êîãäà ÷åëîâåê íàêëîíÿåòñÿ ñòîÿ, âåñ òåëà ïðèõîäèòñÿ áîëüøå íà îäíó íîãó è îäíî áåäðî, â òî âðåìÿ êàê äðóãàÿ íîãà è äðóãîå áåäðî îñòàþòñÿ íåäîãðóæåííûìè. Ðåáðà íà ñòîðîíå íàêëîíà ñáëèæàþòñÿ äðóã ñ äðóãîì, ðàñïîëàãàÿñü ìåæäó îïóùåííûì ïëå÷îì â âûñîêî ïîäíÿòûì áåäðîì; â òî æå âðåìÿ íà äðóãîì áîêó îíè ðàñõîäÿòñÿ. Ýòî ïðèâîäèò ê ñäàâëåíèþ è îãðàíè÷åíèþ ïîäâèæíîñòè ãðóäíîé êëåòêè, íàðóøàåò äûõàíèå è ÿâëÿåòñÿ ïðåäïîñûëêîé ê âîçíèêíîâåíèþ òóáåðêóëåçà.
Ó æåíùèí, ðàáîòàþùèõ ñî ñêëîíåííûì âáîê êîðïóñîì, êàê îòìå÷àåò Koelsch, êóïîë ìàòêè, êàê ïðàâèëî, ñìåùàåòñÿ îò ñðåäíåé ëèíèè òåëà â ñòîðîíó ñêëîíåííîãî âáîê êîðïóñà (âûñîêîðàñïîëîæåííîãî áåäðà); ñîîòâåòñòâåííî ïåðåìåùàþòñÿ è êèøå÷íûå ïåòëè.
ðàáîòà âðà÷à ñòîìàòîëîãà
Ñîãëàñíî Hertz, ïîëîæåíèå êîðïóñà ñ èñêðèâëåííûì âáîê ïîçâîíî÷íèêîì ïðèâîäèò ê ïðèâû÷íîìó ñóæåíèþ ãðóäíîé êëåòêè. Ýòî îòðàæàåòñÿ íà çàïîëíåíèè êðîâüþ æåëóäî÷êîâ ñåðäöà, îò÷åãî ïóëüñ ñòàíîâèòñÿ íåðàâíîìåðíûì. Ñåðäöå ïîëó÷àåò äîïîëíèòåëüíóþ íàãðóçêó; ïðè ýòîì íàáëþäàþòñÿ ðåçèñòåíòíûå òîë÷êè ó âåðõóøêè (Koelsch).
Hertz òàê îáúÿñíÿåò õàðàêòåð âîçíèêàþùèõ ïîâðåæäåíèé. Åñëè ñäåëàòü ïîïåðå÷íûé ðàçðåç ãðóäíîé êëåòêè íà óðîâíå ñîñêîâ, òî ìû îáíàðóæèì, ÷òî ïî ôîðìå îíà íàïîìèíàåò ïî÷êó. Ñàìîå óçêîå ìåñòî â ýòîì ïðîñòðàíñòâå ðàñïîëîæåíî ìåæäó ïîçâîíî÷íèêîì è ãðóäèíîé. Ïðè äåôîðìàöèÿõ ãðóäíîé ïîëîñòè ñåðäöå âíà÷àëå óñòðåìëÿåòñÿ â íàïðàâëåíèè áîëåå øèðîêîãî ó÷àñòêà è ïîýòîìó ñìåùàåòñÿ âëåâî, ÷òîáû îêàçàòüñÿ â isthmus â ìîìåíò ñâîåãî ðàñøèðåíèÿ.
 ðåçóëüòàòå ýòî ïðèâîäèò ê íåèçáåæíîìó ñäàâëèâàíèþ ñåðäöà ãðóäíîé êëåòêîé, ÷òî ïðîÿâëÿåòñÿ ñëàáîñòüþ, ëåãêèì îáìîðîêîì, íåðàâíîìåðíûì ïóëüñîì è ýêñòðàñèñòîëîé, ò. å. íåýêîíîìè÷íûì ðåæèìîì ðàáîòû ñåðäöà. Ñäàâëåíèå ñåðäöà ýëàñòè÷íîé ãðóäíîé êëåòêîé ïðåæäå âñåãî óõóäøàåò çàñàñûâàíèå êðîâè â æåëóäî÷êè, ýòî îòðàæàåòñÿ è íà êîðîíàðíîì êðîâîòîêå, ÷òî ïðèâîäèò ê èçìåíåíèÿì ìèîêàðäà íà ïåðåäíåé è çàäíåé ñòåíêàõ ñåðäöà, ãäå äàâëåíèå äåéñòâóåò íàèáîëåå ñèëüíî. Blickl ãîâîðèò ïî ýòîìó ïîâîäó: «Äûõàòåëüíîìó àïïàðàòó è ñåðäöó ìåøàåò íåáëàãîïðèÿòíîå ïîëîæåíèå, â êîòîðîì ðàáîòàåò âðà÷-ñòîìàòîëîã, îñîáåíïî ïðè íàêëîíå ïîçâîíî÷íîãî ñòîëáà è çàòûëêà.
Ìûøöû ïîñòåïåííî ïðèâûêàþò ê íåïðàâèëüíîìó ïîëîæåíèþ òåëà, êîòîðîå â èòîãå, íåñìîòðÿ íà âñå íàøè óñèëèÿ, âíåøíå âûãëÿäèò íåýñòåòè÷íî è íåãèãèåíè÷íî. Íàêëîíåííîå ïîëîæåíèå êîðïóñà è ñâÿçàííîå ñ íèì äàâëåíèå íà æåëóäî÷íî-êèøå÷íûé òðàêò ïðèâîäÿò ê çàñòîéíûì ÿâëåíèÿì, ïîýòîìó ìíîãèå âðà÷è-ñòîìàòîëîãè ñòðàäàþò æåë÷íîêàìåííîé áîëåçíüþ». Heinrich íàáëþäàë, ÷òî äëèòåëüíûé íàêëîí êîðïóñà âáîê âûçûâàë íåéðîàñòåíè÷åñêèî íàðóøåíèÿ è íåâðîçû ïå÷åíè è êèøå÷íèêà.
Ñäàâëåíèå îðãàíîâ áðþøíîé ïîëîñòè â ñî÷åòàíèè ñ êîíñòèòóöèîííûì ïðåäðàñïîëîæåíèåì âëåêëî çà ñîáîé ýíòåðîïòîç, äèñïåïñè÷åñêèå ÿâëåíèÿ, ãàñòðèò, íåéðî-âåãåòàòèâíóþ äèñòîïèþ, êîòîðûìè ÷àñòî ñòðàäàþò ñòîìàòîëîãè.
Îãëàâëåíèå òåìû "Ïðîôåññèîíàëüíûå áîëåçíè ñòîìàòîëîãà":
1. Ïðîôåññèîíàëüíûå çàáîëåâàíèÿ ñòîìàòîëîãà. Ãðóïïû áîëåçíåé âðà÷à ñòîìàòîëîãà
2. Ïðîôåññèîíàëüíûå íåâðîçû ñòîìàòîëîãà. Áîëè â ðóêàõ ó âðà÷åé ñòîìàòîëîãîâ
3. Ðåâìàòè÷åñêèé ïîëèàðòðèò ó âðà÷åé. Êîíòðàêòóðà Äþïþèòðåíà ó ñòîìàòîëîãîâ
4. Òåíäîâàãèíèò (ïàðàòåíîíèò, ïåðèòåíäèíèò) ó âðà÷à ñòîìàòîëîãà
5. Ìèêîãåííûå ýêçåìû è äèñãèäðîçû ó âðà÷åé. Ãðèáêîâûå ïîðàæåíèÿ êîæè ó ñòîìàòîëîãîâ
6. Ñòàòè÷åñêèå ïîðàæåíèÿ âðà÷à ñòîìàòîëîãà. Ëîêàëüíàÿ áîëü è óñòàëîñòü âðà÷åé èç-çà ñòàòè÷åñêèõ íàðóøåíèé
7. Îñîáåííîñòè ðàáîòû âðà÷à ñòîìàòîëîãà ñòîÿ. Èçìåíåíèÿ ãðóäíîé êëåòêè îò ñòîÿ÷åé ðàáîòû
8. Ãîëîâíûå áîëè ó âðà÷åé ñòîìàòîëîãîâ. Íåïðàâèëüíîå ïîëîæåíèå òåëà ó âðà÷à
9. Òðåáîâàíèÿ è ïîëîæåíèå ñòîìàòîëîãè÷åñêîãî êðåñëà ïðè ðàáîòå âðà÷à
10. Ðàáîòà âðà÷à-ñòîìàòîëîãà ñèäÿ. Òðåáîâàíèÿ ê âðà÷åáíîìó ñòóëó
Âñå ðàçìåùåííûå ñòàòüè ïðåñëåäóþò îáðàçîâàòåëüíóþ öåëü è ïðåäíàçíà÷åíû äëÿ ëèö èìåþùèõ áàçîâûå çíàíèÿ â îáëàñòè ìåäèöèíû.
Áåç êîíñóëüòàöèè ëå÷àùåãî âðà÷à íåëüçÿ ïðèìåíÿòü íà ïðàêòèêå ëþáîé èçëîæåííûé â ñòàòüå ôàêò.
Æàëîáû è âîçíèêøèå âîïðîñû ïðîñèì ïðèñûëàòü íà àäðåñ statii@dommedika.com
Íà ýòîò æå àäðåñ æäåì çàïðîñû íà êîîðäèíàòû àâòîðîâ ñòàòåé - áûñòðî èõ ïðåäîñòàâèì. | {
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-7,672,695,786,948,572,000 | Merck Manual
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Campylobacter Infections
By
Larry M. Bush
, MD, FACP, Charles E. Schmidt College of Medicine, Florida Atlantic University
Last full review/revision Apr 2022| Content last modified Apr 2022
CLICK HERE FOR THE PROFESSIONAL VERSION
• People can be infected when they consume contaminated food or drink or have contact with infected people or animals.
• These infections cause diarrhea, abdominal pain, and fever.
• Identifying the bacteria in a stool sample confirms the diagnosis.
• For some people, replacing lost fluids is all that is needed, but if symptoms are severe, antibiotics are also needed.
Campylobacter bacteria normally inhabit the digestive tract of many farm animals (including cattle, sheep, pigs, and fowl). The feces of these animals may contaminate water in lakes and streams. Meat (usually poultry) and unpasteurized milk may also be contaminated. People may be infected in several ways:
• Eating or drinking contaminated (untreated) water, unpasteurized raw milk, undercooked meat (usually poultry), or food prepared on kitchen surfaces touched by contaminated meat
• Contact with contaminated food or water (for example, when handling contaminated food)
• Contact with an infected person (through contamination of food with fecal material or sexual contact)
• Contact with an infected animal (such as a puppy)
Campylobacter bacteria, usually Campylobacter jejuni, cause inflammation of the colon (colitis) that results in fever and diarrhea. These bacteria are a common cause of infectious diarrhea in the United States and among people who travel to countries where food or water may be contaminated.
Campylobacter jejuni affects healthy and ill people and causes diarrhea in all age groups. It seems to mostly affect children 1 to 5 years of age.
Symptoms of Campylobacter Infections
Campylobacter symptoms usually develop 2 to 5 days after exposure and continue for about 1 week. Symptoms of Campylobacter colitis include diarrhea, abdominal pain, and cramps, which may be severe. The diarrhea may be watery and sometimes bloody and can be accompanied by nausea, vomiting, headache, muscle aches, and fever ranging from 100 to 104° F (38 to 40° C).
Complications
Complications of Campylobacter infection can include
Bacteremia occurs temporarily in some people with colitis. This infection usually causes no symptoms or complications. However, the bloodstream is repeatedly or continuously infected in a few people, usually those with a disorder that weakens the immune system, such as AIDS, diabetes, or cancer. This infection causes a long-lasting or recurring fever.
Other symptoms develop as the bloodstream carries the infection to other structures, such as the following:
Guillain-Barré syndrome (a nerve disorder) develops in about 1 of 2,000 of people with Campylobacter colitis because antibodies that the body makes to fight off the infection sometimes also attack the nerves. Guillain-Barré syndrome causes weakness or paralysis. Most people recover, but muscles may be greatly weakened. People may have difficulty breathing and need to use a mechanical ventilator Mechanical Ventilation Mechanical ventilation is use of a machine to aid the movement of air into and out of the lungs. Some people with respiratory failure need a mechanical ventilator (a machine that helps air get... read more . Weakness does not always completely resolve. About 25 to 40% of people who develop Guillain-Barré syndrome have had a previous Campylobacter infection.
Reactive arthritis may develop days to weeks after the diarrhea resolves. Usually, the disorder causes inflammation and pain in a knee or other joint.
Diagnosis of Campylobacter Infections
• Culture of a stool sample
• Sometimes culture of a blood sample
Doctors may take a sample of stool and send it to a laboratory to grow (culture) and identify the bacteria. However, stool is not always tested. Stool cultures take days to complete, and doctors do not usually need to know which bacteria caused the diarrhea to effectively treat it. However, if people have bloody diarrhea or appear seriously ill, the stool is usually tested. A test that identifies genetic material of the bacteria in stool, called the polymerase chain reaction (PCR) technique, may be used so that the bacteria can be detected more quickly. The PCR technique increases the amount of the bacteria's DNA to make it easier to detect. Other tests may rapidly identify the bacteria (antigen) in the stool.
If doctors suspect that the bloodstream or other organs are infected, they take a sample of blood to be cultured.
Treatment of Campylobacter Infections
• Usually no specific treatment
• Sometimes an antibiotic such as azithromycin
Many people get better in a week or so without specific treatment.
Some people require extra fluids by vein (intravenously) or by mouth.
People who have a high fever, bloody or severe diarrhea, or worsening symptoms may need to take azithromycin for 3 days by mouth. Ciprofloxacin is an alternative but is used with caution because resistance to this antibiotic is increasing.
If the bloodstream or other organs are infected, antibiotics such as imipenem or gentamicin are required for 2 to 4 weeks. The antibiotics used first may be adjusted based on results of the susceptibility tests.
More Information
The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.
• Centers for Disease Control and Prevention (CDC): Campylobacter: A resource providing information about Campylobacter, including outbreaks and antibiotic resistance
Drugs Mentioned In This Article
Generic Name Select Brand Names
ZITHROMAX
CILOXAN, CIPRO
GENOPTIC
NOTE: This is the Consumer Version. DOCTORS: CLICK HERE FOR THE PROFESSIONAL VERSION
CLICK HERE FOR THE PROFESSIONAL VERSION
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8,719,349,175,054,372,000 | Immune inhibitory receptors in host–microbe interaction
Rumpret, Matevz
Promoter:
Prof.dr L. (Linde) Meyaard
Research group:
Meyaard
Date:
March 17, 2022
Time:
12:15 h
Summary
The immune system protects the organism from disease, but inappropriate immune responses can also damage it. Inhibitory receptors can dampen immune responses and prevent tissue damage and inflammatory diseases. In the human genome, genes for over 300 potential immune inhibitory receptors are present. Here, we explore the possible roles inhibitory receptors play in regulating immune responses, in particular the response to bacteria. We suggest two different groups of inhibitory receptors with separate functions and use mathematical models to illustrate their possible modes of operation. We further identify the human S100 family of proteins as the first known ligands for the inhibitory receptor Signal inhibitory receptor on leukocytes-1 (SIRL-1). S100 proteins are released from damaged cells, and we show that SIRL-1 recognises several S100 proteins, suppressing neutrophil ROS production. We suggest that SIRL-1 activation by S100 proteins may help limit tissue damage caused by the immune response. We also show that a group of bacterial peptides, the staphylococcal phenol-soluble modulins, and the structurally and functionally related human peptide cathelicidin LL-37, activate SIRL-1. This suggests that α-helical peptides with an amphipathic arrangement of hydrophobicity may represent a potential molecular pattern recognised by SIRL-1. Furthermore, we argue that also other inhibitory receptors recognise endogenous and microbial patterns. We propose that these inhibitory pattern recognition receptors provide context and help mediate tolerance to microbes and balance responses to danger signals The insights gained here will guide future directions for using SIRL-1 and other inhibitory receptors as therapeutic targets. | {
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5,472,871,490,905,937,000 | 4.03.2018
Healthy Mouth, Healthy Body
It may not seem obvious, but the truth can’t be denied. If you don’t look after your mouth, your body will suffer. Since the mouth is full of bacteria, your gums can easily get infected, which, naturally, leads to a response of the immune system and the gums become inflated. If the inflammation is not treated properly, it will continue to develop and attack the gums and bone structure. This is called periodontitis and as a result, our teeth lose their support and start falling out.
This is the simplest result of neglecting oral hygiene, which means there are other consequences, too. Many serious illnesses can get aggravated or caused by poor oral hygiene, which is why it’s of utmost importance to look after our teeth and mouth. Here are just some of the problems that can occur if you neglect your oral hygiene.
Diabetes
One of the strongest connections between the mouth and body is definitely the one between periodontitis and diabetes. With more and more people suffering from diabetes due to inappropriate diet, lack of exercise or other reasons, there’s really no need to add another risk to the mixture. Once the mouth gets inflamed, the body is no longer able to control blood sugar successfully.
People suffering from diabetes lack insulin, which is the hormone that converts sugar into energy. With periodontal disease, the inflammation affects the body’s ability to utilise insulin. Also, high blood sugar creates perfect conditions for infections to develop. So, make sure you treat gum infections properly, especially if you suffer from diabetes.
Heart problems
Research shows there is significant correlation between gum and heart disease, with the number of people with heart disease suffering from periodontitis being much higher than the number of people who don’t have a heart condition. Scientists are still trying to figure out the exact type of connection, but what we know at the moment is that there are a few risk factors in common, such as smoking, unhealthy diet and obesity.
One of the theories suggests that inflammation in the mouth leads to inflammation in the blood vessels, which can make you more prone to heart attack. Namely, when blood vessels are inflamed, less blood travels between the heart and the rest of the body, which means that blood pressure goes up. Another potential danger is that fatty plaque damages the blood vessel walls, so that blood can even travel to the brain, which can lead to a stroke.
Pregnancy complications
We have all heard about the problems that prematurely born babies have, such as lung and heart conditions and learning disorders. It’s true that there are many factors that influence premature birth, but it seems that infection and inflammation, including those in your mouth, can also be one of them.
That’s why all experts recommend a thorough periodontal exam before or during pregnancy. The sooner the potential problem is identified, the less damaging it will be to both mother and the foetus.
Smoking
With so many negative effects of smoking, it’s pretty obvious that those who can’t give up that bad habit are seriously damaging their health and those of others. When it comes to the connection between smoking and oral hygiene, it’s worth pointing out that smokers are three times more likely to suffer from severe gum disease than non-smokers. That’s because nicotine makes blood vessels constrict, which affects the gums’ ability to fight infection. Even the best cosmetic dentist, like the Australian expert Luke Cronin, whose virtuosity in transforming teeth into beautiful smiles has even been featured in Vogue Australia, needs more time for corrective action to teeth and gums that have been exposed to nicotine over longer periods of time.
Osteoporosis
When talking about bone loss, people usually think of osteoporosis, but periodontitis also leads to the same problem. The difference is that osteoporosis affects the long bones in the limbs, while gum disease affects the jawbone. Also, women are prone to the former, while men are more prone to the latter. Still, recent studies suggest that women with osteoporosis are also more likely to suffer from gum disease than those who don’t have problems with osteoporosis. It could be the case that inflammation caused by periodontitis weakens other bones as well, but scientists are still trying to confirm that theory.
Other conditions
We are witnessing more and more correlations between oral health and general health. Many studies have been conducted and ever more are in progress, examining various mouth-body connections. The links seems to appear with conditions like rheumatoid arthritis, pneumonia, COPD and obesity, to name but a few.
What we know so far is that the health of your mouth affects the health of your body and vice versa. That means that we have to look after our teeth and mouth if we want to prevent other health issues. Paying regular visits to our dentists and oral hygienists is vital if we want to have healthy mouth and body. Also, we should be setting an example to our children that no-one else will look after our health if we don’t do it ourselves.
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-4,333,705,665,932,508,700 | %0 Journal Article %A Fiegler, H %A Gribble, S M %A Burford, D C %A Carr, P %A Prigmore, E %A Porter, K M %A Clegg, S %A Crolla, J A %A Dennis, N R %A Jacobs, P %A Carter, N P %T Array painting: a method for the rapid analysis of aberrant chromosomes using DNA microarrays %D 2003 %R 10.1136/jmg.40.9.664 %J Journal of Medical Genetics %P 664-670 %V 40 %N 9 %X Objective: The authors describe a method, termed array painting, which allows the rapid, high resolution analysis of the content and breakpoints of aberrant chromosomes. Methods: Array painting is similar in concept to reverse chromosome painting and involves the hybridisation of probes generated by PCR of small numbers of flow sorted chromosomes on large insert genomic clone DNA microarrays. Results and Conclusions: By analysing patients with cytogenetically balanced chromosome rearrangements, the authors show the effectiveness of array painting as a method to map breakpoints prior to cloning and sequencing chromosome rearrangements. %U https://jmg.bmj.com/content/jmedgenet/40/9/664.full.pdf | {
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1,297,354,672,348,248,000 | Hearing Associates of Libertyville, IL
Medications that cause hearing loss and tinnitus.
Investigating the side effects of a medication when you first begin taking it is a natural thing to do. You want to find out if you can expect to feel nauseous or if it will give you dry mouth. There is a more serious potential side effect that you may not recognize which is hearing loss. Ototoxicity is the term medical professionals give to this condition. Broken down, ototoxic means ear poisoning.
Exactly how many drugs that can cause this problem is unclear, but there are at least 130 ototoxic medications on record. What are some of the common ones you should look out for and why?
Some Facts About Ototoxicity
How can a pill reap havoc on your ears after you swallow it? Certain drugs can damage your hearing in three different places:
• The stria vascularis – Located in the cochlea, the stria vascularis makes endolymph, the fluid in the inner ear. Too much or too little endolymph has a significant impact on both hearing and balance.
• The cochlea – That’s the seashell-shaped component of the inner ear that takes sound and converts it into an electrical signal the brain can comprehend. Damage to the cochlea affects the range of sound you can hear, commonly starting with high frequencies then escalating to include lower ones.
• The vestibule of the ear – This is the part of the ear that sits in the middle of the labyrinth that makes up the cochlea. It helps regulate balance. Vestibulotoxicity drugs can cause you to get dizzy or feel like the room is spinning.
Tinnitus is caused by some drugs while others cause hearing loss. If you hear phantom sounds, that could possibly be tinnitus and it usually shows up as:
• Thumping
• Popping
• A windy sound
• Ringing
Usually if you quit using the medication the tinnitus will stop. However, permanent hearing loss can be caused by some of these drugs.
What Drugs Put You at Risk?
The checklist of drugs that can cause temporary or permanent hearing loss might surprise you. Many of them you could have in your medicine cabinet right now, and chances are you take them before bed or when you have a headache.
Topping the list for ototoxic medications are over-the-counter pain relievers such as:
• Ibuprofen
• Naproxen
You can add to this list salicylates that you may better know as aspirin. The hearing problems induced by these drugs are generally correctable when you stop taking them.
Coming in a close second for well known ototoxic medications are antibiotics. Some antibiotics are ototoxic but many aren’t. You might have heard of some of these that aren’t:
• Erythromycin
• Vancomycin
• Gentamycin
As with the pain relievers, the problem goes away once you stop taking the antibiotic. Other drugs on the common list include:
• Chloroquine
• Quinidine
• Quinine
Tinnitus Can be Triggered by Several Common Compounds
Edecrin
• Marijuana
• Caffeine
• Tonic water
• Nicotine
When you get up every morning and drink your morning coffee you subject your body to a substance that might cause tinnitus. After the drug leaves your system it will pass and that’s the good news. Some drugs, ironically, that doctors give to treat tinnitus are actually on the list of offenders.
• Prednisone
• Lidocaine
• Amitriptyline
However, the amount that will trigger tinnitus is a lot more than the doctor will generally give.
Ototoxicity Has Specific Symptoms
They vary depending on the medication and your ear health. Mildly annoying to completely incapacitating is the things you can usually be expecting.
Be on guard for:
• Hearing loss on one or both sides
• Vomiting
• Blurring vision
• Tinnitus
• Poor balance
• Difficulty walking
If you have any of these symptoms after using a medication even if it’s an over-the-counter herbal supplement, you should contact your physician.
If you have ototoxicity does that mean you shouldn’t take your medication? You should always take what your doctor tells you to. Don’t forget that these symptoms are temporary. Keep yourself aware by always asking your doctor about the possible side effects of a medication and don’t be reluctant to ask about ototoxicity. You should also schedule an appointment with a hearing care specialist to have a hearing test.
The site information is for educational and informational purposes only and does not constitute medical advice. To receive personalized advice or treatment, schedule an appointment.
Call Now
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-1,631,107,942,800,702,200 | Richard G. Petty, MD
Peripheral Neuropathy
Treating peripheral neuropathy can be one of the toughest problems facing a clinician. Peripheral neuropathy simply means disease affecting the peripheral nerves.
There are a great many cause of peripheral neuropathy. This is just a partial list to give you an idea of the things that a clinician has to think about before starting treatment:
1. Metabolic illnesses: Diabetes mellitus; porphyria; chronic renal failure; amyloidosis and disturbances in circulating proteins
2. Vitamin deficiencies: Vitamins, B1, B3, B6 and B12
3. Drugs and chemicals: Alcohol; Heavy metals like arsenic, lead and mercury; organic pesticides; several drugs used in cancer chemotherapy; isoniazid; nitrofurantoin
4. Infections: Lyme disease; Herpes zoster (shingles); Diphtheria; Brucellosis; Leprosy; Tetanus; Botulism
5. Malignant illnesses
6. Inflammatory and autoimmune illnesses: Rheumatoid arthritis; Systemic lupus erythematosus; Polyarteritis nodosa; Sarcoidosis; Guillain-Barre syndrome; Celiac disease
7. Physical injury: Trauma, stretching and compression of nerves, which can include things like carpal tunnel syndrome.
8. Congenital illnesses
Many causes of peripheral neuropathy, particularly diabetes, may also damage the autonomic nervous system that controls the heart, blood pressure, swallowing, intestinal and bladder function.
Neuropathic symptoms typically start in the feet, because the nerves running down there are longer and more vulnerable than the ones going to the hands.
The most common symptoms are:
1. Numbness
2. Tingling
3. Abnormal sensations called dysesthesias
4. A characteristic form of pain, called neuropathic pain or neuralgia: people usually describe it as “pins and needles,” a steady burning sensation or “electric shocks.” These pains can be difficult to describe: typically pains, like stubbing your toe or stepping on something sharp, are transmitted through pain fibers. Neuropathy also involves other neurological pathways, so that the brain receives impressions that it cannot process.
There has been a revolution in out understanding of neuropathic pain in recent years. It is now considered to be a disease rather than a symptom. Normal pain is designed to protect you: you put your foot on a hot plate and you pull it away immediately. Neuropathic pain is different: it is non-protective and it persists and therefore behaves like a disease.
Multiple different classes of medications have been shown to be effective in some people with neuropathic pain, though most are not approved for use by the Food and Drug Administration:
1. Lidocaine patches and creams
2. Capsaicin creams
3. Opioid analgesics
4. Tricyclic antidepressants
5. Serotonin-norepinephrine reuptake inhibitors (SNRIs)
6. Anticonvulsants: Carbamazepine; gabapentin; pregabalin
Earlier this week, data presented at the European Federation of IASP (International Association for the Study of Pain) Chapters (EFIC) indicated that an innovative combination of painkillers might hold the key to unlocking the severe and relatively untreatable pain of peripheral neuropathy.
Dr Magdi Hanna, Director of Pain Clinical Research Hub at King’s College Hospital in London, has been studying the combination of the strong opioid oxycodone (OxyContin) with gabapentin (neurontin) in over 300 patients with severe diabetic neuropathy. This combination demonstrated a significant 33% improvement on top of the best pain relief achievable using the maximum tolerated dose of gabapentin as monotherapy. The study was part funded by one of the medicine manufacturers.
This study is good news, but even in this study there were a great many people who were not helped. In another blog item, I’m going to talk about some of the unorthodox approaches that have helped some people.
About Richard G. Petty, MD
Dr. Richard G. Petty, MD is a world-renowned authority on the brain, and his revolutionary work on human energy systems has been acclaimed around the globe. He is also an accredited specialist in internal and metabolic medicine, endocrinology, psychiatry, acupuncture and homeopathy. He has been an innovator and leader of the human potential movement for over thirty years and is also an active researcher, teacher, writer, professional speaker and broadcaster. He is the author of five books, including the groundbreaking and best selling CD series Healing, Meaning and Purpose. He has taught in over 45 countries and 48 states in the last ten years, but spends as much time as possible on his horse farm in Georgia.
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1,393,182,996,106,352,000 | Fats are Good and also Bad, Choice is Yours
Fats are Good and also Bad, Choice is Yours
Fat is the reservoir of energy for all the living creatures. There are people trying to lose fat, some avoiding it and a few hiding it but interesting
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Fat is the reservoir of energy for all the living creatures. There are people trying to lose fat, some avoiding it and a few hiding it but interestingly you need fat in your body. Fats can be broadly divided into two types-saturated fats and unsaturated fats based on the arrangement of carbon, oxygen and hydrogen atoms within the molecule.
The difference between these two types of fat:
Saturated fats:
• Remains solid at room temperature
They are not essential to one’s health. These fats are hard to digest and are full of cholesterol. When we talk of a healthy diet, we would either want to avoid it completely or limit the use of the saturated fat. The reason being, increase in cholesterol level in the blood.
Food source rich in saturated fat:
Meat, coconut oil, palm oil, poultry skin, dairy products like cheese, whole cream milk, desserts like pastries, cookies and the list goes on.
Unsaturated fats:
These are further classified into two groups-polyunsaturated fat and monounsaturated fat.
• Liquid at room temperature
Polyunsaturated fats are divided into omega 3 fatty acids and omega 6 fatty acids.
Food sources rich in polyunsaturated fat: Fishes like tuna, salmon and sardines, corn oil, soya bean oil and sunflower oil.
Monounsaturated fat: Nuts like almonds, peanuts, hazelnuts, olive oil and canola oil.
However, some fat is definitely needed in maintaining a healthy body. Fats are a major source of energy to your body as it is needed to dissolve certain vitamins required by our cells. Vitamins like Vitamin A, D, E, and K can be absorbed by the body only when your diet contains fat as vitamins dissolve only in fat. So if you want the benefits of these vitamins, you need to include the right amount of fat in your diet. Both monounsaturated fats and polyunsaturated fats are considered to be good as they help you to lower your cholesterol levels, in turn decreasing your risk for heart diseases. Interestingly consumption of these fats in very little amount can lead to obesity, fatigue and in some cases heart problems.
Fats are Good and also Bad, Choice is Yours
Learn to differentiate between good fat and bad fat:
• Good fats are the naturally obtained fats that are not altered whereas
• Bad fats are the fats obtained from an animal source that is further chemically altered and sometimes they are also found in tropical oils.
The secret to preserve your waistline and protect your health is to understand dietary fats and making good choices.
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2. Ìóòàöèÿ. Ìóòàöèè ó áàêòåðèé. Ìóòàãåíû. Ñïîíòàííûå ìóòàöèè. Îáðàòíûå ìóòàöèè ( ðåâåðñèè ).
3. Èíäóöèðîâàííûå ìóòàöèè áàêòåðèé. Õèìè÷åñêèé ìóòàãåíåç. Ðàäèàöèîííûé ìóòàãåíåç. Òèïû ìóòàöèé.
4. Ðåïàðàöèÿ ÄÍÊ áàêòåðèé. Ñèñòåìû ðåïàðàöèè äíê. Êîìïåíñàöèÿ ôóíêöèé íàðóøåííûõ â ðåçóëüòàòå ìóòàöèé. Èíòðàãåííàÿ ñóïðåññèÿ. Ýêñòðàãåííàÿ ñóïðåññèÿ.
5. Ïåðåíîñ áàêòåðèàëüíîé ÄÍÊ. Êîíúþãàöèÿ áàêòåðèé. F-ôàêòîð áàêòåðèè.
6. Òðàíñôîðìàöèÿ áàêòåðèé. Ñòàäèè òðàíñôîðìàöèè áàêòåðèè. Êàðòèðîâàíèå õðîìîñîì áàêåòåðèé.
7. Òðàíñäóêöèÿ. Íåñïåöèôè÷åñêàÿ òðàíñäóêöèÿ. Ñïåöèôè÷åñêàÿ òðàíñäóêöèÿ. Àáîðòèâíàÿ òðàíñäóêöèÿ. Ôåíîìåí ëèçîãåíèè.
8. Ñâîéñòâà áàêòåðèé. Íåíàñëåäóåìûå èçìåíåíèÿ ñâîéñòâ áàêòåðèé. S - êîëîíèè. R - êîëîíèè. M - êîëîíèè. D - êîëîíèè áàêòåðèé.
Òðàíñäóêöèÿ. Íåñïåöèôè÷åñêàÿ òðàíñäóêöèÿ. Ñïåöèôè÷åñêàÿ òðàíñäóêöèÿ. Àáîðòèâíàÿ òðàíñäóêöèÿ. Ôåíîìåí ëèçîãåíèè.
Òðàíñäóêöèÿ — ïåðåíîñ áàêòåðèîôàãîì â çàðàæàåìóþ êëåòêó ôðàãìåíòîâ ãåíåòè÷åñêîãî ìàòåðèàëà êëåòêè, èñõîäíî ñîäåðæàâøåé áàêòåðèîôàã. Òðàíñäóöèðóþùèé áàêòåðèîôàã îáû÷íî ïåðåíîñèò ëèøü íåáîëüøîé ôðàãìåíò ÄÍÊ õîçÿèíà îò îäíîé êëåòêè (äîíîð) ê äðóãîé (ðåöèïèåíò).
Âûäåëåíî òðè òèïà òðàíñäóêöèè: íåñïåöèôè÷åñêàÿ (îáùàÿ), ñïåöèôè÷åñêàÿ è àáîðòèâíàÿ.  êëåòêå, èíôèöèðîâàííîé áàêòåðèîôàãîì, â õîäå ñáîðêè äî÷åðíåé ïîïóëÿöèè â ãîëîâêè íåêîòîðûõ ôàãîâ âìåñòå ñ âèðóñíîé ÄÍÊ ìîãóò ïðîíèêíóòü ôðàãìåíòû áàêòåðèàëüíîé ÄÍÊ èëè ïëàçìèäû. Âèðóñû îãðàíè÷åíû â îáú¸ìå ãåíåòè÷åñêîãî ìàòåðèàëà â ñîîòâåòñòâèè ñ îáú¸ìîì ãîëîâêè. Åñëè ÄÍÊ áàêòåðèàëüíîé êëåòêè ðàñùåïëÿåòñÿ ôàãîì â íåòèïè÷íîì ìåñòå, òî ÷òîáû îñâîáîäèòü ïðîñòðàíñòâî äëÿ ôðàãìåíòà õðîìîñîìíîé ÄÍÊ, íåêîòîðûå ó÷àñòêè âèðóñíûõ ÄÍÊ «ïðèíîñÿòñÿ â æåðòâó», ÷òî ïðèâîäèò ê óòåðå îïðåäåë¸ííûõ èõ ôóíêöèé. Ïðè ýòîì ôàãîâàÿ ÷àñòèöà ìîæåò ñòàòü äåôåêòíîé. Êîëè÷åñòâî àíîìàëüíûõ ôàãîâ ìîæåò äîñòèãàòü 0,3% âñåé äî÷åðíåé ïîïóëÿöèè.
Îáðàçîâàâøèéñÿ ôàã è åñòü ÷àñòèöà, âûçûâàþùàÿ íåñïåöèôè÷åñêóþ (îáùóþ) òðàíñäóêöèþ. Ïðè òàêîé ôîðìå òðàíñäóêöèè â êëåòêè-ðåöèïèåíòû ìîãóò áûòü âíåñåíû ïðàêòè÷åñêè ëþáûå ãåíû.
Òðàíñäóêöèÿ. Íåñïåöèôè÷åñêàÿ òðàíñäóêöèÿ. Ñïåöèôè÷åñêàÿ òðàíñäóêöèÿ. Àáîðòèâíàÿ òðàíñäóêöèÿ. Ôåíîìåí ëèçîãåíèè.
Ïðè íåñïåöèôè÷åñêîé òðàíñäóêöèè ôàãîì ìîæåò áûòü ïåðåíåñ¸í ëþáîé ôðàãìåíò ÄÍÊ õîçÿèíà, à ïðè ñïåöèôè÷åñêîé ëèøü ñòðîãî îïðåäåë¸ííûå ôðàãìåíòû ÄÍÊ. Íàèáîëåå èçâåñòíûì ïðèìåðîì ñïåöèôè÷åñêîé òðàíñäóêöèè ñëóæèò òðàíñäóêöèÿ, îñóùåñòâëÿåìàÿ ôàãîì. Ïîñêîëüêó ýòîò ôàã ïðè ïåðåõîäå â ñîñòîÿíèå ïðîôàãà âêëþ÷àåòñÿ â õðîìîñîìó áàêòåðèé ìåæäó ãåíàìè, êîäèðóþùèìè ñèíòåç ãàëàêòîçû è áèîòèíà, èìåííî ýòè ãåíû îí ìîæåò ïåðåíîñèòü ïðè òðàíåäóêöèè. Ïðè àáîðòèâíîé òðàíñäóêöèè âíåñ¸ííûé ôðàãìåíò ÄÍÊ äîíîðà íå âñòðàèâàåòñÿ â ãåíîôîð ðåöèïèåíòà, à îñòà¸òñÿ â öèòîïëàçìå, ãäå åãî ÄÍÊ òðàíñêðèáèðóåòñÿ, íî íå ðåïëèöèðóåòñÿ. Ýòî ïðèâîäèò ê òîìó, ÷òî ïðè êëåòî÷íîì äåëåíèè îí ïåðåäà¸òñÿ òîëüêî îäíîé èç äî÷åðíèõ êëåòîê (òî åñòü íàñëåäóåòñÿ îäíîëèíåéíî) è çàòåì òåðÿåòñÿ â ïîòîìñòâå.
Ñâîéñòâà òðàíñäóöèðóþùèõ ôàãîâûõ ÷àñòèö ñëåäóþùèå:
• ×àñòèöû íåñóò ëèøü ÷àñòü ÄÍÊ ôàãà, òî åñòü íå ÿâëÿþòñÿ ôóíêöèîíàëüíûìè âèðóñàìè, à ñêîðåå ¸ìêîñòÿìè, ïåðåíîñÿùèìè ôðàãìåíòû áàêòåðèàëüíîé ÄÍÊ.
• Ïîäîáíî ïðî÷èì äåôåêòíûì âèðóñàì, ÷àñòèöû íå ñïîñîáíû ê ðåïëèêàöèè.
Òðàíñäóöèðóþùèå ôàãè ìîãóò ñîäåðæàòü êàêóþ-ëèáî ÷àñòü õðîìîñîìû õîçÿèíà ñ ãåíàìè, äàþùèìè ðåöèïèåíòíîé áàêòåðèè íåêîòîðûå ïðåèìóùåñòâà (íàïðèìåð, ãåíû óñòîé÷èâîñòè ê àíòèáèîòèêàì èëè ãåíû, êîäèðóþùèå ñïîñîáíîñòü ê ñèíòåçó ðàçëè÷íûõ âåùåñòâ). Ïîäîáíîå ïðèîáðåòåíèå áàêòåðèÿìè íîâûõ ñâîéñòâ ïîëó÷èëî íàçâàíèå ôåíîìåí ëèçîãåíèè.
Ôåíîìåí òðàíñäóêöèè ìîæåò áûòü èñïîëüçîâàí äëÿ êàðòèðîâàíèÿ áàêòåðèàëüíîé õðîìîñîìû, åñëè ñëåäîâàòü òåì æå ïðèíöèïàì, ÷òî è ïðè êàðòèðîâàíèè ñ èñïîëüçîâàíèåì ôåíîìåíà òðàíñôîðìàöèè.
- Òàêæå ðåêîìåíäóåì "Ñâîéñòâà áàêòåðèé. Íåíàñëåäóåìûå èçìåíåíèÿ ñâîéñòâ áàêòåðèé. S - êîëîíèè. R - êîëîíèè. M - êîëîíèè. D - êîëîíèè áàêòåðèé."
Ìåäóíèâåð Ìû â Telegram Ìû â YouTube Ìû â VK Ôîðóì êîíñóëüòàöèé âðà÷åé Êîíòàêòû, ðåêëàìà
Èíôîðìàöèÿ íà ñàéòå ïîäëåæèò êîíñóëüòàöèè ëå÷àùèì âðà÷îì è íå çàìåíÿåò î÷íîé êîíñóëüòàöèè ñ íèì.
Ñì. ïîäðîáíåå â ïîëüçîâàòåëüñêîì ñîãëàøåíèè. | {
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2,281,173,072,404,789,200 | 0 4 min 8 mths
The customer genomics industry has quickly expanded previously couple of years, because of the recognition of ancestry services and elevated efficiency in DNA collection methods. People are now able to discover the strategies of their genetic blueprints with elevated speed and precision. What this signifies for that industry in general is exploring new avenues to make use of these details for delivering lucrative consumer-driven services. While ancestry might have opened up the doorway, the physical fitness industries are poised is the next wave of genomics services.
Advancements in study regarding fitness’ genetic components have started gradually registering within the public awareness. Whereas previous methods to fitness and workout basically recommended effort and self-discipline, the nascent field of fitness genomics is popping that notion on its mind. Instead of advocate a tough work most importantly approach, fitness genomics is centered on choosing the best workouts and fitness regimens for people according to their genetic marker maps. Rather from the standard, one-size-fits-all approach, fitness genomics rather seeks to optimize every individual’s in-born abilities and inclinations.
Many people are naturally pre-disposed to become better marathon runners than sprinters, other medication is naturally efficient weightlifters while some find it difficult to get ripped and definition. This variations aren’t located in insufficient effort but instead variations in genes. For instance, the ACSL1 gene continues to be formerly associated with affecting your body’s capability to metabolize fat. There are a variety of the way to evaluate these fitness-related markers.
First, there’s the apparent full genetic collection and SNP testing way in which companies perform for his or her suite of services, including fitness. Another approach would be to assess an individual’s phenotypes. Phenotypes would be the bodily traits expressed by specific gene combinations. For people searching to understand physical traits they are able to enhance without delving in to the much deeper genetic roots, phenotype analysis is really a practical path to explore and something that fitness genomics can make money from in general.
When a person’s genome is examined plus they uncover what markers affect them, the next thing is interpreting that information and putting it to make use of. Utilizing a proprietary formula, the organization provides consumers having a set fitness score, based on a number of genetic markers affecting muscle fiber development, metabolizing fat, oxygen usage, etc.
This score will be accustomed to help consumers to select from a number of exercises made to help optimize their own health by emphasizing individuals markers’ positive attributes. Rather of trying to find the right workout through learning from mistakes, people are now able to stay with workouts that play for their genetic strengths. Both workout effort and time are reduced while results improve.
With wearables and also the Internet of products gaining ground both in popular culture and also the consumer market, moving this data to consumers for planned action may be the next logical step. Personal health apps and wearables being able to access this data for daily workout usage is really a strategy consumers will adopt.. | {
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9,194,974,420,784,667,000 | In the latest case of “too much of a good thing,” can you imagine a time when your dentist might tell you to stop brushing your teeth? Although this will probably never happen, if your teeth are showing signs of tooth abrasion, they may ask you to lighten up just a little. Keep reading to find out just what tooth abrasion is and how you can prevent it (or stop it from progressing).
What causes tooth abrasion?
Tooth abrasion is one of several types of dental conditions that can cause teeth to wear away faster than normal. Tooth abrasion occurs as a result of outside forces acting on the teeth, most commonly vigorous and aggressive tooth brushing, often with a hard-bristled brush. This abrasion is also caused by overuse of toothpicks which can create ridges in the teeth.
There is also evidence that tooth abrasion may be a result of the kinds of toothpaste a patient uses (in combination with vigorous brushing). The increased use of abrasive toothpastes can be compared to using an abrasive cleanser to clean the sink. Just like the cleanser removes grime, the abrasive toothpaste can remove grime plus a little bit of enamel each time. Over time, this can cause excessive wear.
Finally, in the too-much-of-a-good thing department, brushing too often can cause tooth abrasion.
Other types of tooth wear
Other types of unnatural wearing of teeth include tooth erosion, tooth attrition, and abfraction.
Tooth erosion occurs when teeth are used for something other than biting and chewing. They are not meant to be used as bottle openers, nut crackers, tool holders, string cutters, or nail trimmers. These common uses of teeth cause far more wear-and-tear per occurrence than do natural uses like eating, yet people often discount the damage they are doing.
Tooth attrition is a type of wear that is caused by tooth-on-tooth contact. In addition to jaw pain and other symptoms, people who suffer from bruxism are familiar with this excessive wear.
Finally, abfraction is a less common type of wear that occurs on the tooth at the gum line. Excessive forces from bruxism are the primary cause.
It can be difficult to judge how much wear is too much. A good measure is if it causes cosmetic concerns or causes pain or discomfort. While some wear of the teeth is natural over time due to normal use, too much wear can lead to potentially serious dental issues.
Tooth abrasion symptoms
Unlike the symptoms for other types of excessive wear, tooth abrasion symptoms are most often present at the gum line. They may appear as a groove or a pocket in the tooth, and you may even be able to feel a groove in the tooth with your tongue as it progresses.
If left untreated, tooth abrasion can rapidly wear down the enamel of your teeth. Tooth enamel is the hardest substance in the human body, but it’s vulnerable over time. Once it’s gone, it cannot be replaced. Enamel protects the sensitive inner pulp of the tooth (the dentin), and when that is exposed you may begin to feel sensitivity to hot and cold temperatures.
If your vigorous tooth brushing is the primary cause, you may also begin to damage gum tissue. This can lead to vulnerability to infection and even abscess.
How to prevent tooth abrasion
Tooth abrasion prevention deals mostly with making changes to your oral hygiene practices.
First of all, don’t put down your toothbrush; change the kind you pick up. Most cases of tooth abrasion begin with a hard-bristled toothbrush. If that’s the case for you, pick up a soft-bristled brush before you do anything else. This alone can help prevent further tooth abrasion.
Once you have your soft-bristled toothbrush, ask your dentist for a proper toothbrushing tutorial. Turns out, there is a better way to brush your teeth. Less of a tooth scrubbing and more of a gentle tooth and gum massage, using the proper toothbrushing technique can go a long way towards limiting further tooth abrasion.
Using a special toothpaste with extra calcium (usually a whitening toothpaste, but ask your dentist) can help the remaining enamel become stronger. Remember to floss once a day and follow other oral hygiene practices as recommended by your dentist.
Finally, limiting sugary and acidic beverages and foods can prot | {
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5,666,821,446,463,853,000 | add share buttonsSoftshare button powered by web designing, website development company in India
Month: September 2020
Importance of Hand Sanitization
You might have discovered that there are individuals who fall sick very often. You could also discover that in certain households, it's normal to find individuals suffering from the common cold and other similar ailments. Not lots of men and women realize there are several basic actions to follow to protect themselves from common disorders.
Maintaining basic hygiene is a simple step towards maintaining good health. Have a shower frequently. The frequency of shower is dependent upon your working conditions and the weather you reside in. As an example, in case you've got a job with a higher amount of physical activity, you might have to bathroom twice to encourage body hygiene. If you want to buy alcohol hand sanitizer in bulk then you can visit https://www.safetysupplies19.com/sanitizer.html.
Importance of Hand Sanitization
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You need to use a premium excellent hand wash liquid since they don't include the germs of another individual's hands. Equally significant is that the time spent during hands wash. Luckily for people who frequently proceed, hand sanitizer is a terrific choice to maintain hygiene.
You receive sanitizer in most varieties of packaging like a little one you may keep in your pocket, a slick one you can keep in your car, and a huge bottle with a dispenser which you may keep on your workplace. It's a really handy product for cases if you don't have time or an alternative to get a suitable hand wash.
Clothes frequently contain hidden germs and bacteria which has the potential to cause us injury. Clean your clothes many times, particularly towels and handkerchiefs. You might also like to include exceptional additives to your washing machine to be certain a thorough wash.
Guidelines to Choose a Good Family Dentist
One of your biggest concerns as a parent is to find medical professionals and dental right to take care of your loved ones. There are so many different suppliers for you to choose from that it can seem as if you will never have enough time to find what you need. Do not let this discourage task to find a family dentist that everyone in your home is very comfortable.
If you want to improve your chances of finding the best practices you need to start with a list of highly recommended professionals. You can easily find out the family dentist in Portland at https://cedarcreekdentistry.com/.
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If you are not sure where to get your recommendations, you can go online on the website of the Portland Dental Association and look for suppliers or get recommendations from your previous dental provider for a good family dentist. No matter how good their grades and comments, you must determine yourself whether a particular practice or not going to be a good fit for you and your family.
Contact several professionals who are on your list and make an appointment for each of you, your spouse and your children. It is important that you do not base your decision on your experience alone, because you are not the only one who needs dental care.
Know About Your Roofer
A roof is one of the most important parts of your property. Regardless of whether it leaks, has ineffective insulation, or is damaged in less obvious ways.
It is essential to repair it to avoid higher insurance costs and electric or gas bills. The roofing contractor is the best choice. You can choose the best nearby roofing organization through the internet.
Selecting the Right Metal Roof in Five Simple Steps
Listed below are some factors you ought to consider prior to hiring a roofer.
Ask for Referrals
The ideal method to make sure you are hiring a reputable roofing company is always to ask your coworkers, family, and friends for references.
If they have employed a roofer and have been happy with their work, it is likely you'll also be satisfied with their work.
Collect Multiple Estimates and Check References
Additionally, it is best to get several estimates to confirm whether or not a contractor is overcharging you. Even so, do not just pick the contractor who gives you the lowest estimate. Be sure the estimate incorporates labor, supplies, as well as the time it is going to take to finish the project.
Moreover, as soon as you have received estimates, ask all the roofing companies who submitted estimates to provide references. Get in touch with these individuals and ask them if they were satisfied with the roofer's service.
Tips For Choosing An Electrician
Electrical services are needed for various purposes. We need electricity directly from the installation when a home or commercial complex is built for the later stages for maintenance.
Due to uninterrupted electricity is something that allows us to carry out our daily functions smoothly, the reliability of the connection is very important. Alongside reliability, functionality and safety is another very important parameter. You can hire an expert electrician via online sources.
How do you choose a reliable electrician?
Electrician must be licensed: One of the basic verifications you need to do when choosing an electrician is that it must be licensed. This ensures that he is skilled and experienced. Having a knowledgeable electrician work to minimize stress and ensure safety.
Electrician must be insured: Before you use the electric service or electric company, you will need to ensure that the person is insured. This will save you from complications in case of an accident at your place.
Electricians SEO - Digital Marketing Agency Sydney Australia
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Check the qualifications: Make sure that the electrical work for you has the relevant qualifications. Electricians must have the required certification to provide services.
Verify that works for you: When you use the services of electricity, there are various types of electrical and interns who were to work for you. Many times it may so happen that the company employed may not have sufficient staff available and May subcontracted tasks. Therefore, it is important that you verify that it will work for you and whether members of a team of qualified, licensed, and insured.
Check recommendation: It is a good idea to verify the recommendation of electricity. You can ask your friends or the people in your social circle for reference of electricity whose services they may have used.
Where to Get Affordable Color Printing
Today's modern digital graphics call for quality color printing. However, extravagant color prints do not come cheap. A heavy price tag comes with a good print. However, while printing photos, posters, and cards, money should not be the only thing that needs to be considered.
The best choice when it comes to affordable color printing is always the one that provides superior quality at a reasonable price. You can find the best information about affordable color printing services by searching over the internet.
Where to Get Affordable Color Printing
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There are many ways to acquire affordable color printing. For starters, you can start your search by finding the most efficient inkjet printer available in the market. Big names in this category are Hewlett Packard, Epson, and Canon.
When choosing a printer to provide affordable color printing, you have to consider several factors. Ease of use and compatibility with your existing software and hardware are two things you should be concerned about.
When picking up printers to deliver cheap color printing, you need to think about many elements. The simplicity of use and compatibility with your current hardware and software are a couple of things that you should be concerned about.
But, investing in a machine isn't necessarily the best choice. If you were planning to print just a few picture functions, it isn't a good idea to have a pricey printer that will finally just collect dust in your workplace. In these cases, you're better off delivering your layouts into the printers and allow them to publish your layouts for you.
At this time, there are numerous businesses whose primary field of business is creating quality prints. This is the very best alternative for you if you do not need to publish images designs and photographs every so often.
Quality prints do not need to be costly. When you look hard enough, then you will surely find great but very affordable color printing hardware or services provided using a device or business close to you.
3 Reasons Why You Should Choose Bath Salt From Amazon
Bath salt is very easy to find in stores. In fact, it can be found at almost any supermarket or department store. But many of the bath salts that you buy in stores may not be as good as the bath salts from Amazon.
What makes dead sea salt so much better than others? The first reason is that it comes from a natural source, meaning it contains no additives, fragrances, or dyes.
Another reason to choose bath salt from Amazon is that it is made of the purest and highest quality ingredients. This includes sea salt, which is a very rare and expensive mineral in the world today.
These are just two of the reasons why this type of salt is special. There are also other great qualities of bath salt from Amazon, including:
Because of its unique sea salt, which comes from only one source, this is the type of salt used by the ancient Egyptians. Some types of sea salt come from the Red Sea, the Pacific Ocean, and the Gulf of Thailand.
Antioxidants are something that people tend to overlook when shopping for beauty products. With bath salt from Amazon, antioxidants are not something to discount. Not only do the antioxidants to help keep your skin healthy, but they will also help your skin become smooth and radiant.
It was in these countries that people learned the benefits of red wines. In India, for example, the skin absorbs the minerals from the wine better than anything else. It also contains amino acids, which fight the free radicals that are responsible for skin aging.
Not only that, but sea salt also is not processed. Even though most of the salt from the Dead Sea comes from mined salt, there is nothing "processed" about it.
The third reason why bath salt from Amazon is more important than other types of salt is that it is not available in regular stores. It is not available anywhere.
You have to go to the Amazon to find the products that contain the best natural remedies for your skin. With the products that are available in Amazon, you can rest assured that your skin will be nourished and glowing.
When it comes to spa quality of treatment, nothing can compare to what is available at the Amazon. It is a great place to get your body and your skin into a top-notch condition.
In addition to being considered to be a spa, Amazon bath salt is also referred to as Himalayan Salt. It is 100% natural, and it is very good for you.
Dental Implant Procedure And Recovery
Many dental patients are concerned when they hear the word dental implant. This recovery device shouldn't be too scary. Dentists use it to help maintain healthy teeth and maintain people's ability to chew, talk, and enjoy life.
Dental patients may find many preparations necessary before implantation from the best dental implant in Brooklyn, NY. The oral surgeon must identify the correct position, shape, and structure of the jaw and mouth. For example, depending on the location of the implant in the future, it may be necessary to identify the proximity of the sinus cavity or below the alveolar nerve canal in the jaw.
dental implants
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In addition to regular dental X-rays, a CT scan of the area may be required. It is necessary to know the exact shape of the jaw and the amount of bone the implant can support to avoid complications, but also to prepare the implant to fit properly.
After planning is complete, the oral surgeon can begin the actual procedure. An incision must be made in the gum above where the implant will be placed.
The implant is inserted without further permanent decoration. Time must be given for natural bone to grow over it and to place it firmly in its place. Then, the prosthodontist can place a crown or other prosthesis over the implant.
Simple Ways To Improve Your Health
Just about everyone wants to be healthier but fewer people actually take the steps to get there. The truth is becoming healthier takes work but there are a large number of things you can do to make it a little easier. One of these things is taking supplements.
A lot of supplements advertised to be effective in increasing weight loss or strength are overly hyped and have no true merit in being effective. In this article, I will list supplements that have been shown to improve your body and enhance your health in different ways. If you want to know more about vitamin C, then visit https://ismile.ee/pood/c-vitamiin-d-vitamiin/.
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If you are overweight one of the first priorities you should have is to lose weight. Of course, you should eat healthily and exercise in order to do this but there are additional steps you can take to lose weight using supplements.
One supplement that has actually been shown to help with weight loss is fish oil. Fish oil offers a number of health benefits and has been proven to be particularly good for your cardiovascular system.
There have also been studies showing that fish oil may improve the way the heart uses oxygen making it more efficient. Additionally, weight loss has indeed been shown to be one of the benefits of fish oil.
Vitamin C is a very important nutrient and not having enough vitamin C can be very costly to your health. It is also something that studies have shown to help with weight loss.
Know The Health Benefits Of Vaughan Pizza
When most people think of pizza, they assume that it is junk food that they can not have very often if they want to be healthy. This can potentially be true, but there is a surprising range to what pizza can do to and for you. If you are interested in good health but can not bear to give up this fantastic food, you will be happy to know that you can actually get some pretty great health benefits as part of the package when you call for pizza delivery in Vaughan.
You can click here to order freshly prepared cheese-burst pizza online.
pizza
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Researchers have actually gone so far as to check out how often people eat this food and what kind of relationship that has to their health outcomes. The results were surprising. They found that people who ate it frequently actually did slightly better than people who did not, in spite of assumptions that eating so much bread and cheese was probably not the best move.
It is important to keep in mind, though, that these results came from people who were eating the sort of pizza that is readily available in Italy, not what you ordinarily get from Vaughan pizza delivery. Still, it is a solid proof that it is possible to benefit from eating such delicious food.
When you are looking for the best pizza delivery in Vaughan for your needs, you should take a look at what Menulog has to offer. The site is designed to give you access to a wide range of establishments in your area, along with extra information like reviews and the details of special deals that are in progress.
Looking at reviews is a wonderful way to find a place to buy food that is both healthy and delicious because you can learn from the experiences of other customers. Whether someone says their food tasted great or they ended up with something incredibly greasy, you will be able to put that knowledge to work in helping you to figure out which option is going to do the best job of meeting your needs.
Explained: Credit Card Debt Consolidation
If you consolidate your credit cards, then you're essentially putting all the debts out of several cards on a single card, like moving everything to a single loan.
The perfect situation is to get a card which has better conditions than the ones that you currently have, since you then not only simplify the number of unique payments you need to make within a month, you also receive a better speed that will assist you to repay your debt. You can get help from the experts in Credit Solutions Company.
This is one way you can save yourself some serious money and look after your debts. Credit card issuers will vie for your company, therefore it's not impossible to locate a card to move all your accounts to that's better terms than the ones that you presently have.
The principal goal here would be to repay your debts, naturally, but the simplification of your bookkeeping is a significant benefit.
Together with each one your debts transferred into one card with better conditions, conditions, and prices, you don't run the danger of missing among your monthly payments as you had too many and lost track of one, hence further increasing your debt.
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If you shut out a workable, fixed-rate credit alternative, then you're restricting your choices. Zero accounts are great.
Whenever you're ready to start consolidating your debt, the very initial step would be to telephone your banks and explain exactly what you wish to do. | {
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794,458,908,332,376,800 | I. INTRODUCTION The histological structures of the mucous membrane of the small intestine. The micro-circulation of blood of the mucous membrane of the small intestine. The lymphatic circulations of mucous membrane of the small intestine. The sympathetic innervation of the intestinal uvulas. The sympathetic stimulation and micro-circulations of the mucous membrane of the small intestine. The model of the circulation of the mucous membrane of the small intestine in rabbits. Calculation of the flow of blood toward segments of circulation. The absorption’s model of the mucous circulation of the small intestine. The clinical importance of the dissertation. II. MATERIALS AND METHODS Experimental animals. Operational process. Calculation of flow. III. RESULTS Variability of the mucous flow. Probability. Comment of results. Initial post-vagotomy's reaction of the duodenal mucous membrane and jejunums. Influence of a hypoxia on the post-vagotomy's circulation of the duodenal and the jejunal mucouse membranes, and vice versa. Influence of a hypercapnia on the postvagotomical reaction. IV. DISCUSSION V. CONCLUSION AND SUMMARY VII. LITERATURE VIII. SUPPLEMENTS The goal of this work is an answer to the question, whether, and under which conditions, a vagotomy can stop bleeding out of the mucous membranes of the duodenum and the small intestine. It is known that vagotomy opens a-v anastomosis in the mucosa and submucosa of the stomach producing an ischemia of the most superficial layers (1, 2,). Spanner described the existence of such anastomosis also in intestinal mucosa of men, rats and in submucosa of dogs (3). Bell and Battersby with clearance of radioactive Krypton-85 proved that vagotomy reduces the blood flow through the mucous membrane of stomach for 29 -74 %, depending upon completeness of intervention and reactions experimental animals (4). So they confirmed works of others authors that vagotomy reduces the total blood flow (5, 6,) and the mucosa blood’s volume (2). Vagotomy prevents grow the blood flow after stimulation of the front hypothalamus (7). On the base of these and others understandings were made the first both-sides truncal vagotomies with piloroplastics for stopping massive bleeding from the most superficial layers of gastric mucous membrane (8). In the master's thesis: “The modified selective vagotomy as a supplement to surgical treatment of erosive gastritis" I presented my experiences with implementation of vagotomy in the treatment of massive bleedings caused by acute erosive ulcerations of the gastric mucous membrane. (Zagreb, 1981.) From the large scientist interest is the influence of vagotomy on the perfusion of duodenal and jejunal mucous membranes. Therefore, we decided for an experimental scientific investigational work from this area. How frequently, concomitantly in the same time together with the gastric mucous membrane, bleeds also the duodenum and the jejunum (erosive gastroduodenitis and gastroduodenojejunitis), investigation of influence of vagotomy on the perfusion of mucous membrane latter has alsop the clinical importance. If it is identical that on the mucous membrane of stomach "The modified selective vagotomy” could be an operation for the bleeding from intestine too. I. INTRODUCTION For the understanding of this work is necessarily to get acquainted with the histological structure of the mucous membrane of small intestine, her microcirculation and the sympathetic innervations, especially with the influence of sympathetic stimulation on the redistribution of blood flow and models of circulation at rest, ingestion, digestion, strengthened motility and other. With comparison of the known with results of our investigations, we will carry out conclusions about the influence of vagotomy on the perfusion of the duodenal and the jejunal mucous membrane. II. HISTOLOGICAL STRUCTURES OF THE MUCOUS MEMBRANE OF SMALL INTESTINE The wall of the small intestine makes mucous membrane, submucosa, muscular layer and serosa. The last three layers are permeated with unique system of crossing collagen fibers. THE MUCOUS MEMBRANE consists of epithel, lamina propria and muscularis mucosae. CIRCLE’ WRINKLES (plicae circulares Kerkringi) are best developed in the distal part of the duodenum and proximal the jejunum, while in the ileum they become gradually all smaller and thinner, and gradually disappear. They are built of the mucous membrane and one part of the submucosa. INTESTINAL UVULAS (villi intestinales) cover complete internal surface of the small intestine. They are long 0,5 to l,5 cm, dick 0,l mm. They are outgrowth of epithelium and laminas propria. They freely stick out in the lumen. On 1 mm² of surfaces have them around 30, total several millions. Between uvulas are opens of intestinal glands. EPITHELIUM of the small intestine is single-layer with two type cells. Most numerous are cylindrical or resorption’s cells. Less numerous are jug’s cells. Cylindrical cells are high about 20 micrometers (microns). They are very elastic, and can easily adapt to all changes. Theirs cytoplasm is finely granular or honeycomb, towards theirs functional’ condition. Their core has placed in the basal part of cells. Theirs surface is covered with 1 -1,5 mm of the fat coating that consists densely compressed shoots of cytoplasm (mikrovili). They are long 1 mm, with the diameter about 0,1 µm (the micrometer). They are increasing the surface of the cylindrical (resorption’s) cells about 14th times. In every mikrovila enters a zone of microfilaments, which occupies theirs centers. The jugs’ cells are put among cylindrical cells. In the jejunum are they less, in the ileum more. On the free surface, they have no coatings. THE epithelium with intestinal uvulas enters in Lieberkühn’s crypts, i.e. intestinal glands (glandulae intestinales) and coats them. Those are simple tubular glands long 0-2 to 0,5 mm, placed in the lamina propria. Cylindrical cells are in them are something shorter of those on the surface of intestinal uvulas and they are constantly mitotic dividing, enabling the regeneration of the intestinal epithelia. For Lieberkühn’s crypts in the small intestine are characteristic Paneth’s cells, which are coming individually, or in groups, on theirs bottoms. They have a round core. Theirs cytoplasm are filled with numerous acidophil granules. Ultra-structurally, at the surface, can be seen mikrovili. At the bottom of Lieberkün’s crypts, there are still yellow cells, which characterize fine granules in the basal part of cytoplasm, which stain with chromic salts yellow. Yellow, enterocromaffin, or basal granulated cells, are belonging to the group of endocrine cells of the gastrointestinal system. In different parts of the digestive system they are intended to various secretor roles (they secretes serotonin, gastrin, secretin, pankreozimin and enteroglukagon). Some are placed in the base of the intestinal epithelia and have no link with the lumen (endocrine cells of the closed type), and others are connected wit the lumen (endocrine cells of the open type). These last possess mikrovili, which can be very long and which receive informations from the lumen on which basis they secrete theirs granule in surrounding capillary spaces. Some of those endocrine cells are morphologically and functionally related to cells of Langerhans’ little islands of pancreas, so a part of researchers count these cell in the unique “gastro-enteral-pancreatic” (GEP) system. THE LAMINA PROPRIA of the small intestine fills uvulas and the space between Lieberkühn’s crypts. It is built of the reticulated tissue, which contains many free cells. On some places, it is filled with a dense mass of lymphocytes, so we speak about the lymph tissue, which comes in two forms: as single lymph little knots (Payers’ plates in the ileum). Besides it, lamina propria contains large number of plasmas’ cells, eosinophilic leukocytes, an some mast-cells. Special kind cells of the laminana propria are so-called globular’ leukocytes, which are emphasizing with theirs round granules, or beads, which color with eosin red. Men give them immunity’s importance. THE MUSCULARIS MUCOSAE enables moving the mucous membrane of small intestine. It comprises of two layers of the smooth muscular cells: interior’s mostly circular and outer longitudinal. Between bundles of smooth muscular cells is a network of fine elastic fibers, which crosses in the propria. Smaller bundles of the smooth muscular cells enter in the propria of intestinal uvulas and inside it lay down parallel with the longitudinal axle. With its contraction, the uvula shortens and pushes the blood and the lymph from them in larger blood and lymph vessels. THE DUODENUM has very tall circle wrinkles with dense thickset uvulas on the surface and special kind of glands, which there are not in others parts of the small intestine. That are Brunner glands – the duodenal glands (gl. duodena1es). They are built like the gyrate ramified tubular glands. With larger part they go through muskularis mucosa and fill out the larger part of submucosa. Their drainage canals open in intestinal crypts, or between uvulas. Brunner glands are built of mucous cells similarly to pyloric glands. They secrete bright mucous excrete which contains proteolytic ferments, and participate at splitting of carbohydrates. Ultrastruktural contains a rich endoplasmic small net, numerous mitochondria, very large Golgy system, and numerous secreting granules of which ones are zymogene and the second mucous. THE JEJUNUM. In the upper part of jejunum circle wrinkles are high and numerous, similarly in the duodenum, but towards the ileum they become shorter having all bigger interspaces. Uvulas are long and some more flattened. In the epithelium of the distal part of the jejunums jug cells are especially numerous. The lymph tissue is represented in the form of little single lymph knots in the mucous membrane (9). THE VILLUS INTESTINALIS is the small protuberance like lobule. It is high 0,5 -1,5 mm. It is spread out widely whole the small intestine. It is built of the connecting basis, which makes the skeleton of uvula. In this basis have a lot of lymphocytes and some individual leukocytes. In the middle of the uvula is the central lakteal. Around it are two or more arteries (central arterioles), which go towards the top of the uvula, parallel with the central lakteal. On the top of the uvula arteries cross in a capillary network, and one twig goes directly in the vein as arteriovenous anastomosis. This anastomosis is important for functioning of the heart, because in no-digestive phase blood directly over the anastomosis goes in the vein and does not spend any energy for pushing blood through the capillary system. The smooth muscular fibers of uvula come from the muscular layer of the mucous membrane, go parallel with the longitudinal axle of uvula, and come to its top where they catch for the basal membrane of the epithelia. When this muscular fibers contract it empties and the again erects by the blood (9). THE MICROCIRCULATIONS OF THE MUCOUS MEMBRANE OF THE SMALL INTESTINE Large central arterioles of the villuses (intestinal uvulas) start from the submucosa’ arteries, and go parallel with the central lakteal (the hilus’ sinus) towards the top of the villus without branching. Nearby the top every the central arteriola gives two branches. The one as pre-capillary arteriola go parallel with the curve of the top and crosses in the subepithelial capillary net, which connects with the subepithelial capillary layer of marginal arterioles. The second, something distanced of the top of the uvula, crosses in the central vein. Capillaries of the upper branch go through the capillary subepithelial layer from the top of the uvula towards the base flowing into, in middle parts of the uvula in the central vena. Through this direct arteriovenous anastomosis between the subepithelial capillary layer and the central vena empty also capillaries of the subepithelial layer of basal parts of the villus which is continuation of the capillary layer of the region of crypts, in which blood flows from the base towards the direct arteriovenous communication in the middle part of uvula (2,111). Two or more small branches of submucosal arteries penetrate the muskularis mucosa and enter in the region of crypts. Here, form the capillary net, which extends up to basal parts of the villus continue in the subepithelial capillary layer. Less pre-capillary arterioles go directly towards the subepithelial capillary layer as marginal arterioles (2, ll). THE LYMPH CIRCULATIONS OF THE MUCOUS MEMBRANE OF THE SMALL INTESTINE The absorbed liquid accumulates in the interstitial tissue where from blood and lymph capillaries take away it. Hydrostatic and the oncotic pressure have the crucial role in the drainage of this liquid. The drainage ability of these systems are fascinating (13). The model of blood and lymph microcirculations, shown in the Fig. 7, shows some details that characterized the architecture of the villus. 1. Villus’ capillaries are 0,5 – 2,0 micrometer of the basal membrane of the epithelial cover. They create the capillary subepithelial layer thick 2,0 µm. 2. The fenestrations of the capillary endothelia are on the side of the basal membranes and communicate with the subepithelial and the juxtacapillary interstitial lymph space. 3. The central lakteal is located average 50 micrometers of the basal membrane of mucous epithelial layer. 4. The space within the villus, between arteries, represents the interstitial lymph space in which collects absorbed liquid. Many think that via subepithelial juxtacapillary space takes away majority of absorbed liquid. (The lymph capillary layer is analogous to the blood subepitelial capillary layer.) Accumulation of liquid in the interstitial tissue leads to: 1. Growth of the volume of the interstitial liquid; 2. Growth of the interstitial hydrostatic pressure, and 3. to decrease of interstitial of the oncotic pressure. The interstitial tissue is composed of the collagen threads and mucopolysacharides mutually interwoven in the gelatinous mass. The hydraulic conductivity normally hydrated interstitial tissue is very small. As the volume conductivity vice versa proportional to concentration of the hyaluronic acid, the growth of the volume of liquid increases the hydraulic conductivity of the interstitial tissue. The hydrostatic pressure increases too. The oncotic pressure falls. The capillary filtration stops. Filterable capillaries turn into absorptive. The lymph’ vessels are filling with the liquid. During absorption oncotic lymph pressure falls with 1,3 kPa (10 mm Hg) – normal – on 0,3 to 0,9 kPa (2 to 7 mm Hg). Fall of the interstitial oncotic pressure for 0,3 to 0,9 kPa (2 to 7 mm Hg) depends on the level of water absorption. Conductivity of the interstitial tissue is, therefore, larger what its volume is bigger. (The oncotic pressure is reduced). By it the capillary conductivity and permeabilitet remains unchanged. Divisions of the interstitial tissue on central and the juxtacapillary part ensure the passive flow of liquid in capillaries. The hydrostatic pressure is in juxtacapillary areas much more sensitive on a change of the volume in the central interstitial spaces of the villus. Therefore, larger part of the absorbed liquid takes away hereby and this passively in capillaries. The largest fall of the interstitial oncotic pressure appears just in that subepithelial-juxtacapillary part. 40 % of absorbed liquids are taking away with lymph vessels, dependently on: 1. The pressure of the intra-lumen liquids in lymph vessels; 2. The portal pressure; 3. The mobility of the small intestine and 4. The blood pressure of arterioles and capillaries. The interstitial hydrostatic pressure moves liquid through the tissue and large pores of walls of limph vessels. The flow of lymph maintains valves of lymph vessels and the gradient of the hydrostatic pressure. Of help is also active contractions of arteries (inside factors) and the mobility of intestine, and contraction of villus (outer factors). The fall of the pressure in the central lakteal and collection of accumulated vessels makes easier filling (the distension pressure). Gastro-intestinal hormones (cholecystokinin and secretin) instilled in the a. mesenteric superior are increasing the intestinal flow of bloods and lymph. Turner and Barrowman think that hormones exuded during absorption increase the capillary perfusion and the pressure in capillaries. Increased capillary filtration increases amount of liquid in the interstitial tissue. Cholecystokinin and secretin would so accelerate the flow of lymph, preventing transforming exuding capillaries in absorptions’. The amount of the absorbed waters via lymph roads can vary from 1 to 85 %. At the normal portal pressure, blood capillaries remove the larger part of absorbed volume. Blood capillaries fills also the hydrostatic and oncotic pressure, while lymph only hydrostatic. At increased the portal pressure is reduced evacuations via blood. The hydrostatic pressure grows, as also evacuation with lymph. Because of a stoppage are growing capillary filtration. Lymph vessels remove also the additional interstitial volume. After meals or intralumenal applications of nutrients increase the interstitial flow for 30 up to 130 %, causing a postprandial intestinal hyperemia. The absorbed liquid increases the capillary hydrostatic pressure. This, on the other hand, reduces the pressure of the interstitial tissue on capillaries. The oncotic pressure of plasma falls. The capillary’s perfusion and permeabilitet grow. In the absorptive phase, therefore, absorbed liquid spreads the interstitial space, increasing the hydrostatic pressure and reducing the oncotic pressure. Changes are causing a reverse flow: from interstitial tissue in the blood. Filterable capillaries convert in absorptive. Grows production of lymph and accelerates the lymph flow (13, 14,). SYMPATHETIC INNERVATIONS OF THE INTESTINAL UVULA Noradrenergic fibers flow along blood vessels. The muskularis mucosa and the submucosa are especially well innervated. Dense plexuses surround arterioles in the region of crypts from which threads ascend in the hillus. Together with central arterioles, they go along the central lakteal. On the top of the uvulas, they branch, creating dense tangles of subepithelial capillary layer of the villus top and base-lateral membranes, whose terminations terminate in capillaries. Noradrenergic threads are found also between epithelial base-lateral membrane and capillaries. However, these fibers never noticed beside the epithelium. Exceptionally they could be viewed together with capillaries (15). Absorptions of liquid is under influence of noradrenalin. Alpha-adrenergic agonists (Field and Mc Coll, 1973), exogenously given noradrenalin (Fields and Mc Coll, 1973, Hubel 1976, Levens and coworkers 1979), and stimulations of the simpathetical threds in jejunum (Brunson and coworkers 1979) increase absorption of liquid. Alpha-adrenergic antagonists interrupt with noradrenalin-encouraged absorption (15). Noradrenalin directly influences on the ion’s pump on the epithelial base-lateral membrane (Fields and coworkers 1976). It also influences on the flow of blood in the area of crypts, and in the villus. Probably it influences also on the lymphatic system of the villus with contraction of smooth musculature. Noradrenalin liberated in the tissue around capillaries diffuses in this, and via the blood comes on the second places, even in cells of the epithelium, which alone are not noradrenergic innervated (l5). The smooth musculature of the villus is well noradrenergic innervated. Levens and coworkers (1979) are opinion that alpha-receptors on base-lateral membrane of the epithelial cells tie noradrenalin liberated at terminations and accelerate transport of liquid. (Results are identical those got after implementation of angiotensin II (Levens and coworkers 1981). Blood vessels of the region of crypts are very well innervated, as well as connections capillaries and varicoses in vicinity of the base-lateral membrane. Threads, which accompany the central lakteal, have the crucial influence on the smooth musculature (15). SYMPATHETIC STIMULATIONS AND MICROCIRCULATION OF THE MUCOUS MEMBRANE OF THE SMALL INTESTINE Stimulation of the noradrenergic fibers of the villus lowers lymph flow, coefficient of capillary filtration, and the capillary pressure. Also reduces the pressure of the interstitial circulation. This means that during stimulations of the sympathicus there is no "self-regulation" no one of these elements (l6, 21). Stimulations of fibers of the small intestine promptly reduces blood flow, which after gradually returns in normal frames. Arterioles and venulas contract balanced actively. Because of these biphasic answers come up to relative weak fall of capillary pressure. Intestinal flow promptly falls on 48,3 beside oscillations about 7 %. (Later increased on 73,7 with oscillations of 4,2 %.) Coefficient of the capillary filtration reduces for 75 %. The adrenergic stimulation increases the total intestinal resistance for 47 %. Grows are caused wit increasing of the pre-capillary resistance. Growth of post-capillary resistance is insignificant. During sympathetic stimulations grows the lymphatic oncotic pressure, which indicates the intestinal dehydration (l7). The sympathetic nerve system plays an important role in reflex control of the blood volume. The reflex activation of the sympathicus in the answer on hemorrhage causes vasoconstriction and grows pre- and post-capillary resistance. As, result of segmental changes of vascular resistance capillary pressure falls, and the interstitial liquid is absorbed in the vascular system for purpose of restoration of blood volume (the "auto-transfusion") (18). Maintenance approximately constant capillary pressure during stimulations of the sympathicus considers important for protection of delicate function of the alimentary canal in the preventing intestinal dehydration (19, 20,). Tonus of pre-capillary sphincters seems that plays deciding role in reduction of capillary flow (l8). Reduced transport’s capacity of the intestinal microcirculation lows filtration. Lundgren and coworkers have noticed growth of the absorption of liquid and electrolytes during stimulations of the sympathicus (18, 20, 22,). Others authors (Shepherd AP and coworkers) have confirmed that sympathetic stimulation closes pre-capillary sphincters. Decrease of capillary flow lower giving oxygen to tissues on the level of diffusion (23, 24). Some works (Gidda JS and coworkers) show that vagotomy has any effect on the electric activity of the small intestine. Conclusion: n. vagus influences excitatory and inhibitory. Inhibitory influences are dominant in an intact intestine (25). MODEL OF THE MUCOUS CIRCULATION OF THE SMALL INTESTINE AT RABBITS How our experimental work is worked on rabbits we must get acquainted with the model of theirs circulation. It is practically identical to man’s. The theoretical model of vascular net the small intestine in rabbits has been built by injecting with the silicone foam and polystyrene micro-granules (Lewitt of DG and coworkers, 1979). The same authors have confirmed with this an earlier opinion that the blood flow in the area of crypts is independent about the flow in villuses. This was completely understandably because those are two areas with different functions (26). Big central arterioles start from sub-mucous arteries and accompany the central lakteal to the top of the villus, or near it, without branching. Two or more branch of sub-mucous arteries go through muskularis mucosa and enter in the region of crypts. Here form the capillary network, which communicate with the sub-epithelial capillary net of villuses. This network belongs to marginal arterioles which branch in the capillary sub-epithelial layer. Near the top of the villuses, or in alone tops, the central arterioles give two branches: one pre-capillary arteriole, which follows the curve of the villus branching in the capillary sub-epithelial layer of the top. Over the capillary networks, this layer connects with marginal arterioles –sub-epithelial capillary layer of the basal and the middle parts of the villus. The second branch of the central arteriole is something more remote of the top and crosses in the central vein. This is a -v connection on the top ("by-pass"). Capillaries of the first branch empty through direct a-v communications in the central vein in the middle part of the villus. Through these communications are emptying the capillary sub-epithelial layer of lower parts. This means that the circulation in the capillary sub-epithelial layer of upper parts of villuses go in the direction from tops toward the base, and in the distal parts from the bases towards tops. (At the rat the central arterioles give two pre-capillary arterioles which crosses in the sub-endothelial capillary layer. There is no direct a-v communication on top.) At the value of the pressure of 13,3 kPa (100 mm Hg) in the aorta, the pressure in arteries on relation aortas-intestine falls on 7,6 kPa (57 mm Hg). In the intestinal wall in intramural arteries measures 20 micrometers falls on 0,8 kPa (6 mm Hg), in order to then gradually increases as follows: on relation on mucous arteries measures 20 micrometers 2,0 kPa (15 mm Hg), in order to in mucous arterioles would have been 2,9 kPa (22 mm Hg). CALCULATION OF THE FLOW OF THE BLOOD IN SEGMENTS OF THE CIRCULATION Lewitt DG and coworkers are calculated the blood flow in segments of circulation. They used POISEUILLE law. Beside the constant viscosity the segmental resistance is directly proportional relationship to length, and reversely proportional to the radius on fourth. l = the length r = the radius The segmental resistance = l/r on 4 (radius on fourth). The segmental resistance is therefore directly proportional to length, and reversely to radius on fourth. Length and radius of the blood vessels was determined microscopic. It was studied 50 villuses. (The Rabbit had the weight of 1 kg.) The average height of villuses was about 500 micrometers (400 – 800 micrometers). Radius of central vein was between 5 to 8 micrometers. Radius of central arterioles was about 5 micrometers, terminal arterioles and capillaries 2,5 to 4,0 micrometers. Distributions of mucous flow in the model were calculated by analysis of the circulation’s networks under the microscope. Throughput was determined from the value of the blood pressure and the segmental resistance in intramural veins measures 20 micrometers. The mucous pressure was 2,9326 kPa (22 mm Hg). The absolute mucosa throughput through villus was 5,37 x 10 on -5ml/min (ten on the minus 5). Number of villuses in a gram intestine was 2,2 x 10 on fourth. The mucous throughput through the gram intestine we can get if the absolute mucous throughput through one villus multiply with number of villuses in the gram intestinuma. It is 1,18 ml/min. The intestinal flow we can get if to this worth we add the non-mucous intestinal flow in the gram of tissue (5 % of the intestinal flow under normal conditions). It is 1,24 ml/min. All is calculated on the normal arterial pressure of a rabbit of 12,7 kPa (95 mm Hg). The presumable pressure loss through the system circulation is 0,9 kPa (7 mm Hg). l2,7 kPa minus 0,9 kPa is 11,6 kPa. (95 mm Hg minus 7 mm Hg is 88 mm Hg.) By the calculation of the segmental flow was used the relationship: Pressure = flow x resistance. The throughput in the region of crypts is 44 %, and in the region of villuses 56 % of the total mucous flow. With contraction of the central arteriole reduces its diameter. The capillary pressure falls. For example, by the decrease for 30 %, the capillary pressure in the theoretical model of circulation falls for 1,2 to 1,5 kPa (9 to 11 mm Hg). In the same time the mucous flow falls with 1,l8 ml/min on one gram of the intestine on 0,81 ml/min/gr. The throughput through the region of crypts grows with 44 % on 60 % of the mucous flow. The throughput through the region of villuses falls with 56 % on 38 % of the mucous throughput. Pressure in central and marginal arterioles grows with 3,9 kPa on 4,4kPa (with 29 on 34 mm Hg). At the mucous throughput of 0,81 ml/min/gr intestine, the intestinal throughput is 0,90 ml/min/gr. Difference refers on the non-mucous intestinal flow and on growth of the capillary pressure for 0,13 kPa (1 mm Hg) or less, what is additional time’s effect, because of changes of the blood pressure in the smallest arteries. The absolute resistance of the mucous throughput calculated with Poseuille law, respecting known sizes, is 54653,0 kPa (4,1. x 10 on 5 mm Hg). Pre-mucous resistance is 40 % of the absolute: 21861,2 kPa (1,64 the x 10 on 5-in the mm Hg). The resistance of branches of the central arterioles is 98642,0 kPa (7,4 the x 10 on 5-in the mm Hg), marginal arterioles 239940,0 kPa (1.8 the x 10 on 6 in the mm Hg). For the mucous perfusion are importance resistances: l. Central arterioles; 2. Marginal arterioles; 3. Capillaries; 4. Pre-capillaries arterioles and a-v connections; 5. Central veins. 56 % of the total mucous throughput enters mucosa via the central arteriole (through villus). Two-thirds of it (38 % the total throughput) go via "by-pass" on the top of the villus in the central vein. Only a third (1.8 % of the total throughput) runs through sub-epithelial capillary network. 44 % of the mucous throughput goes via marginal arterioles. The very small part relates on the circulation in the region of crypts. The throughput in every sub-epithelial capillary area (4 distal steps of the model) is 2-4 % of the total flow. The largest part relates on upper steps – the top of the villus. The villous capillary throughput is uniform – equal in all villuses. The throughput depends on the segmental resistance. The largest part of the total mucous resistance relates on the arterioles. If the resistance in central and marginal arterioles reduced on 0 (widely dilated), and the pressure stays the same, the throughput grows for 139 %. If the resistance falls in all else vessels except arterioles the throughput grows only for 80 %. If we reduce the resistance in the mucous throughput, the perfusion increases only for 33 %. In order to reduce the perfusion more than for two-thirds is necessary strong contractions all trio of arterioles, majorities capillaries (with open "by-pass"), with relating contraction of the central vein. Three quarters of the total intestinal resistances relates to pre-mucous blood vessels. Therefore, the throughput of the mucosal resistance is not altering the perfusion as much as a growth of the pre-mucosal resistance. Shutting of the CA in the region of crypts reduces the mucosal throughput for 54 %. If the CA is closed in the region of villuses, decreasing is only 2l %. Closing of marginal arterioles in the region of crypts reduces the mucosal throughput for 43 %. Increasing or decreasing of resistance in the CA has the large effect on the villus throughput, and very small in the region of crypts. At the marginal arterioles are vice versa. If the resistance in the CA reduced from 16 (normally 1) on 0,2 (the diameter grows of 0,5 to 1,5; normally 1), and others resistances remain unchanged, the villus capillary throughput grows rapidly from 37 % on 147 % (the normal flow 100 %). If the resistance in the marginal arteries reduced in the same proportion the growth of the villus capillary throughput is considerably smaller. THE ABSORPTION MODEL OF THE MUCOUS CIRCULATION OF THE SMALL INTESTINE Postprandial hyperemia is the complex phenomenon. It is caused with neural, humoral and local factors. In phases of the ingestion is noticed a prompt mesenteric vasoconstriction. During digestions, postprandial, the blood throughput gradually grows, in order to reach maximum about one hour after ingestion. It maintains for hours after. The blood throughput is doubled. Beside mucous arterioles are dilated also all else arteries (27). Atropine weakens the postprandial hyperemia (27). A blockade of alphas- and betas- receptors does not disturb the mechanism of the postprandial hyperemia (27). Cholinergic blockade weakens vasodilatation. It also prohibits the excretion of intestinal hormones. Vagotomy prohibits excretion of these hormones. Directly after the operational intervention, vagotomy weakens postprandial hyperemia. A fatty meal, in the experiment whole milk or the wheat oil, causes the hyperemia not just of windings in which the meal is instilled, than in neighboring windings too. The model of the circulation is similar to that, which we get after intra-arterial infusion of secretin or the cholecystokinin. The food, which contains a bit of greases and proteins cause a hyperemia only in the winding in which is applied (27). With instillation of 5 % and 10 % the solution of glucose in 9 % the NaCl we get the model of the metabolic intestinal mucosal hyperemia. (Sodium enables an active transport of glucoses.) The local anesthesia of the examined windings weakens the hyperemic effect intra-luminal applied glucoses. This suggests the nerve influence on the postprandial hyperemia. Hyperemic answer depends also about osmosis possibility of meals. What this is bigger more strength is hyperemia (27). With motility induced hyperemia, as well as at the skeleton’s musculatures, causes the hyperemia of the muscular layer of the mucosa (27). Absorbed liquid reduces concentration of intestinal proteins. Trans-capillary concentration’s gradient grows. Also accelerates circulation of lymph (27). THE CLINICAL IMPORTANCE OF THE WORK Hemorrhagic duodenitis and jejunitis are not rare how it is thinking. The mucous membrane of the small intestine often bleeds together with the mucosa of the stomach. Causes of the hemorrhagic lesions both are the same. Upper parts of gastrointestinal tract frequently bleed at chronic renal diseases (28). Some medicines can cause fatal bleedings: tolazolin for example in the neonatal period (29}. Cirrhotic patients also gladly bleed. Some racial groups are specially disposed toward the hemorrhagic enteritis. So is described the special clinical entity at Turks (30). Parasitic diseases are the further cause of hemorrhagic enteritis (31). Described is cases of the massive bleeding from the gastrointestinal tract at Recklinghausen disease (32). Oldsters generally bleed more easily than young people. The protein loosing enteropathy often finishes lethal because of the massive bleeding in mukoe the course of the erosive jejunoileitis (33). Very dangerous bleeding duodenitis and jejunitis are described after operational interventions on the spinal marrow and large blood vessels (34, 35, 36, 37, 38, 39, 40,). A massive intestinal bleeding can also cause yersinia pseudotuberculosis (41). Stopping the massive bleeding from mucosal lesions of the small intestine is the big problem. Extensive resections are not permit. Therefore possible stopping such bleedings with vagotomy would be of the big clinical importance. II. MATERIALS AND METHODS Experimental animals. After Lewit DG and coworkers, 1979 years, were built the theoretical model of vascular network of the mucosa of the small intestine of rabbits, it became an experimental animal of choice for studying the mucous circulations at men. CA gives, namely, as in men, two branches: one that makes the direct arteriovenous connection between the CA and CV, and the second that, as a pre-capillary arteriole crosses in the sub-epithelial layer. At the rat, CA gives two pre-capillary arterioles, which both crossing in the sub-epithelial capillary layer. Lewite DG and coworkers calculated also the throughput of the blood in segments of the circulation. By that, using Poiseuille law, on which, beside the constant viscosity SE (segmental resistance) = l/radius on 4 (l =length). The length and radius of the blood vessels they determined by microscope. They used a rabbit of 1,0 kg. They studied 50 villuses. The transversal height of villuses was 500 micrometers (400 - 800 µm). Radius of CV was between 5 to 8 µm, CA around 5 µm, terminal arterioles and capillaries 2,5 to 4,0 µm. Distribution of the circulation was presented in the introduction. . This conceives enabled calculating the blood throughput in segments of the circulation in the same model and after vagotomy. Therefore, the rabbit is the experimental animal of this work. It wereused rabbits of 3,0 kg with the Department for the pharmacology, which otherwise were used for student’s exercises. Reactions of these animals on the pharmacy-drugs of the autonomous nervous system and on hormones of the gastrointestinal tract secretin and the cholecystokinin are identical as at man (14). The work was made on 16 experimental animals. Ten experimental animals were used for the creation of main work, and others six for the testing of the initial reaction, and an influence of vagotomy on hypoxic and hypercapnic circulation. Tested was also the influence of vagotomy on the hypovolemic circulation, as on the redistribution of the throughput. Obtained results enabled studying of the influence of hypoxia and hypercapnia on the post-vagotomic circulation. Presented is the mucous throughput 1, 3, 10, 20, 30, 45, 60 and 90 minutes after vagotomy. Operational procedure. Animals were narcotized with 25 % solution of Urethan. It was given 0,9 mg on 1 kg of bodyweight intravenous in the vein of an ear. After introduction of an animal in narcosis followed a cut through the derma, subcutaneous tissue and pre-tracheal fascia, with what was presented trachea, through that was brought a permanent plastic cannula for a undisturbed breathing. The venter was opened with the median laparotomy. At all animals double-sided trunk’s vagotomy was performed. After mobilization of the abdominal oesophagus, this was completely cut several centimeters above the cardia and removed in the length of 1 to 2 cm together with the adjacent oesophageal tissue and both vaguses. Samples of the duodenal and jejunal mucous membrane and were taken in certain intervals before and after vagotomy. Supply and drains’ blood vessels were occluded. In this way was prevented a discharge of the circulative volume by taking of samples for histological investigation. 15 - 30 minutes after putting samples in the fixative liquid (10 % solution of formalin) clamps were removed, and the sample (in the whole circumference of the length of 2 - 3 cm) were cut on two half because better fixation. In the purpose of presenting of an influence of vagotomy on hypoxic and hypercapnic circulation of an isolated winding of intestine, and vice versa, was used a device for the extracorporeal circulation. By help of the device for the extracorporeal circulation, in a canulated a. mesenterica cranialis, was applied the solution of colored gelatin the same viscosity with blood (500,0 ccm physiologic NaCl, 50,0 gr of gelatin and 30.0 gr of "intensive chine ink"). Used liquid was previously warmed on 37°C. The histological preparations were made in the Department for the histology of the Medicine faculty in Zagreb and in the Department for the pathological anatomy and the histopathology of the Military hospital in the Zagreb. Investigated were 195 samples of the mucous membranes, altogether 1.600 microscopic preparations. Calculation of the throughput. The circulation network was studied by a microscope. For each examined the segment of circulation (CA, CV, MA, a-v "by-pass", and others) was studied 50 villuses in which the same was best presented. There were measured lengths and widths of villuses, diameter of central lacteals, CA, CV, and-v "by-passes" on the top, capillaries, a-v "by-passes" in the middle, MA and a-v "by-passes" in the region of crypts. Lengths were calculated towards Lewit’s rabbit (with proportion and conversion’s factor). Obtained results were checked under the microscope. From lengths and radius were calculated SR (segmental resistance) and carried out necessary conclusions. From the length and widths of villuses were calculated lengths others tested elements. Lengths tested elements of the Lewit’s rabbit: CA 500,0 µm – conversion factor towards the length of the villuses l,0. CV 500,0 µm - conversion factor towards the length of the villuses 1,0. A-V "b-p" on the top of villuses 180,0 µm – conversion factor towards the length of the villuses 1,4. Capillaries 80,0 µm - conversion factor towards the length of the villuses 0,16. A-V "b-p" in the middle 100,0 µm – conversion factor towards the length of the villuses 0,76. MA 100,0 µm - conversion factor towards the length of the villuses 0,2. A-V "b-p" crypts - conversion factor towards the length of the villuses 0,9. After calculation of lengths, by help of the relationships SR = l/r on 4, were calculated segmental resistances of tested segments of the circulation and carried out necessary conclusions. From tables of frequencies were calculated indexes and percentages of decrease or magnifications of all investigated variables. The throughput was calculated as follows: Volumes of vilues were calculated by formula for the roller: V = r² . 3,14 . v Number of villuses in the gram of tissues was calculated by proportion towards the volume numbers of villuses at Lewit’s rabbit. The throughput through the gram of the mucosa before the vagotomy is constant and is 1,18 ml/min/g. The throughput through the gram of the intestinuma before vagotomy is constant and is 1,242 ml/min/g of tissues. The through through one villus was calculated dividing of the mucous throughput through the gram of tissue with the number of villuses in one gram of tissue. The throughput through the region of crypts of one villuses was calculated dividing the mucous throughput through the region of crypts with number of villuses in the gram of tissues. The throughput through the region of villuses of one villuses was calculated dividing the mucous throughput through the region of villuses with the number of villuses in the gram of tissues. The throughput through the region of crypts, before vagotomy, is 44 %, and through the region of villuses 56 % of the throughput through the region of villuses. The throughput after vagotomy was calculated by proportion towards earlier presented results of Lewitt’s work:The radius of CA is decreased for 30 % what reduces the mucous throughput with 1,l8 ml/min on 0,81 ml/min/g. In the same time the throughput through the region of crypts grows with 44 % on 60 % of the total mucous throughputs. For the calculation of the throughput was used following relationships: r/x 31,4 /100 – (---)on 2 . 100/. ----- r/o 51 Q/xm = (--------------------------------) • Q/o 100 Q/ xm = the mucous throughput in ml/min/g of of tissues in the determined time’s interval after vagotomy. Q/o = the mucosa throughput through one gram of tissue in ml/min/g before vagotomy /1,18/. r/x = radius of CA in the determined time’s interval after vagotomy. r/o = radius of CA before vagotomy. 31,4 = the fall of the throughput in percentages at taper of CA for 30 % (more correct 31,36). 51,0 = percentage’s decrease of the cross-section of CA at decrease of radius for 30 %. Qxk = (44 + 16/31,36 • x) • Qxm/100 Qxk = the throughput through the region of crypts in the gram of tissues in the determined time’s interval after vagotomy. 44 = the percentage of the throughput through the region of crypts before vagotomy. 16 = the increase of the throughput in percentages through the region of crypts at decrease of the mucous throughput for 31,36 %. x = the percentage of reduction (or increases) the mucous throughput through the gram of tissue determined time’s interval after vagotomy. Qxv = (56 – 18/31,36x) • Qxm/100 Qxv = the mucous throughput through the region of villuses in the determined time’s interval after vagotomy. 56 = the percentage of the throughput through the region of villuses before vagotomy. 18 = decrease of the throughput in percentages through the region of villuses at decrease of the mucous throughput for 31,36 %. Qxi =(Qxm/19) • 20 Qxi = the intestinal throughput through the gram of tissues. From tables of frequencies was carried out the statistical processing of results. There were calculated the arithmetic midpoints and measured variability. Determined is P = the statistical probability, as measures of a chance of appearing. III. RESULTS The amount of dates does not allow theirs complete presentation. Therefore, we decided to present only variables and theirs arithmetic’s midpoints, which are indispensable for understanding of the work, and carried out of the statistical batch processing. That is tables of frequencies of arithmetic features, and variability of measured characteristics, and verisimilitudes as a chance of appearing determined reactions. How it is going for the verisimilitude system (not determined) were used statistical methods. Hypothesis of the work is reductions of circulation after vagotomy. Reducing circulation and its redistribution is a happening that not have to happen obligatory (stochastic correlation). Verisimilitude, as for this the most appropriate statistical method, measures a chance of appearing, and has a value from 0 up to 1. (1 = happening must appears; 0 = impossible event.) m P = --- n P = verisimilitude m = number of favorable outcomes n = number of total possible outcomes Variability of measured characteristics features is presented in tables of variability of the mucous throughput in ml/min/g of tissue. Variability of others features is not presented, although it is discussed in tables of the arithmetic midpoints (in the supplement). Variability of the radius of central arterioles is in the linear correlation with variability of the mucous throughput in ml/min/g of tissue, so that a special presentation is not needed. In all tested cases appeared a strong reduction and redistribution of circulation, so P = 1, what means that hypothetical set event must appears. VARIABILITY OF THE MUCOUS THROUGHPUT in ml/min/g of tissue: I. 1 3 10 20 30 45 60 90 D +0,747 +0,309 -0,101 -0,094 -0,221 -0,089 +0,298 -0223 J +0,18 -0,03 -0,193 -0,197 -0,142 -0,086 +0,085 -0,050 etc. PROBABILITY m P = --- n P = probability n = number of total possible outcomes m = number of favorable outcomes P 1 3 10 20 30 45 60 90 D 0,7 1,0 1,0 1,0 1,0 0,9 0,9 1,0 J 0,6 1,0 1,0 1,0 0,9 1,0 1,0 1,0 m = 8 n = 8 P = 1 – happening must appears. System becomes determined. Satisfies mathematical processing of dates. ANALYSIS OF DATES 1 to 3 minutes after vagotomy duodenal villuses lengthened with 421,56 on 523,09 µm (24,08 %). Width of villuses increases with 130,50 on 141,30 µm (8,28 %). Increased also the radius of the central lakteal with 8,0 on 8,37 µm (4,62 %}. Radius a-v "b-p" on the top increased with 4,41 on 4,83 µm (9,52 %), capillaries reduced with 1,69 on 1,65 µm (2,37 %), CA with 2,65 on 1,59 µm (40 %), CV with 4,13 on 3,48 µm (15,74 %), MA with 2,02 on 1,99 µm (1,49 %). Radius a-v "b-p" in the middle increased with 2,55 on 2,59 µm (1,57 %}, and in the region of crypts with 6,70 on 6,93 µm (3,4 %). Changed also SR (segmental resistance), and it: CA with 48,91 on 198,93, CV with 3,l6 on 5,76, "b-p" on the top with 3,57 on 0,44, MA with 4,76 on 8,72 and capillaries with 7,87 on 13,05. Segmental resistance a-v "b-p" in the middle reduced with 5,84 on 3,27. In the first three minutes after vagotomy happened importance redistributions of the throughput. Contraction of pre-capillary arterioles reduced the throughput through capillary areas. SR of CA grows for 306,73 %, and CV only for 82,28 %. SR "b-p" on the reduced for 99,88 %. How the capillary resistance grew for 65,82 %, majority of blood that in the CA arrives directly from the big vessels in submucosas increasingly directs with "b-p" on the top in CV. SR MA grew for 83,19 % (CA for 306,73 %), while a-v "b-p" in the middle was lowered with 5,84 on 3,27 (44,,01 %). Through this "b-p" and marginal arterioles directs relative larger throughput than through the top of the villuses. Vagotomy reduced the total mucous throughput, intensifying at the same time the throughput through all "b-p" -es. A-v "b-p"–es in the area of crypts opened with the diameter of 13,86 µm. (Before of vagotomy 1 µm.) Majority of the circulative blood, 1 to 3 minutes after vagotomy, directed through this connection (0,437 ml/min/g). The throughput through the region of crypts was so puffed up on the account of the throughput through villuses (0,224 ml/min/g). Secretive capillaries are turning into resorptive. Organism adapted on the hypovolemia, resorbing s and draining the intestinal liquid via "b-p" in the middle of villuses. Reaction is identical that in the hypovolemic shock. Redistribution of the throughput through the mucosa of jejunums 3 minutes after vagotomy is similar to duodenal. Lengths of villuses reduced with 579.18, before vagotomy, on 528,82 µm after. Width of the villuses increased with 1l3,94 in the first minute on 140,44 µm in the third. Radius CL is increased on 8,85 µm (6,97 before the vagotomy, and 7,38 one minute after). Radiuses CA (3,82 - 2,73 – 3,18}, "b-p" of tops (5,41 - 5,33 – 5,02), capillaries (1,98 - 1,82 – 1,38), "b-p" of the middle of the villuses (2,97 – 2,70 -2,25), MA (2,23 - 2,05 – 1,83). Radius CV in the first minute is reduced with 5,05 on 4,19, in order to in third would have increased on 5,94 µm. "B-p"-es in the region pf crypts were widen opened with the diameter of 16,88 µm in the first minute, and 17,88 µm in the third. The segmental resistance of CA, in relation to that before vagotomy increased 46,95 times, CV 13,1 times, "b-p" on the top 4.39 times, in the middle 3,5 times, capillaries 4.32 times. Here is also the throughput through all "b-p"-es accelerated. How SR capillaries were increased only 4.3 times, and MA 1,8 times, we concluded that vagotomy guards the circulation of the basal layers of villuses. Secretive capillaries were turning into absorptive. 1 to 3 minutes after vagotomy carried out a strong reduction and redistribution of the throughput. Blood was increasingly directed through a-v "b-p"-es. The largest part went via "b -p"-es in the region of crypts, whose diameter increased with 0,01 µm before vagotomy on 17,88 µm in the third after vagotomy. It is useful to mention that SR of these "b-p"-es was only 0,06 in the first minute and 0.035 in third. Progressively declining of SR on the direction of CA - "b-p" on the top, CV, as well as the relative growth of SR of capillaries and pre-capillary arterioles undoubtedly points out the strong redistribution of the reduced throughput in benefit of deeper layers. In the third minutes after vagotomy the throughput through the mucosa of jejunum was 0,627 ml/min/g of tissues, of which through the region of crypts 0,418, and vilusa 0,190. The throughput through the mucosa reduced for 46,98 %, of which through the region of crypts 19,67 %, and through the region of villuses (most superficial layers) for 71,19 %. In 10th minutes after vagotomy changes of decrease and redistributions of flow are continuing. Radius CA duodenal villuses reduced on 1,48 µm, "b-p" on top on 4,15 µm, CV on 2,79 µm, capillaries on 1,22 µm, a-v "b-p" in the middle on 1,98, MA on 1,53 µm. A-v "b-p" in the region of crypts was still open (radius 7,39). SR of CA grows with 6,88 on 284,66 (41,37 times), CV with 1,47 on 83,54 (56,83 times); and-v "b-p" on the top with 0,34 on 56,91 (167,38 times), and-v "b-p" in the middle with 4,83 on 1200,86 (248,63 times), MA with 5,68 on 192,80 (33,94 times) and capillaries with 4,53 on 98,63 (21,38 times). The smallest growth of the relative segmental resistances we had at capillaries (21,38 times), then at MA (33,94 times). Follow CA (41,37 times), CV (56,83 times}, "b-p" top (167,38 times) and "b-p" in the middle (1200,86 times). As the resistance in capillaries grew only for 21,38 times, and SR "b-p" in the middle of villuses for 1200,86 times, the blood beside progressive strong reduction of the throughputs was kept in capillaries. Organism resisted to emptying of capillary spaces. This conclusion is a result of analyses of the arithmetic midpoints. Organism, namely, in particular cases really resisted to emptying of capillary spaces with strong contraction of drained vessels. In our material, it happened only once, then, when reduction of circulation was the largest. In all rest cases SR "b-p" in the middle of villuses progressively declined, with 4,83 before the vagotomy, on 10,56 in 10th minute after it. Drainage of the blood hereby progressively increased. So was increased the absorptive function of capillaries. (Were reduced the hydrostatic and oncotic pressure.) Only in one case, SR of the draining a-v “b-p” in the middle of the villus grew insomuch average that the average for all experimental animals gave different results. If we compare others sizes (in length and widths of villuses with diameter CL, radiuses arteries we will see that in that case (the first experimental animal, the rat, not rabbit, tested for comparing) achieved bigger reductions of all elements (rabbits), with it the throughput too. The average throughput of the mucosa of duodenum in 10th minutes after vagotomy is 0,634 ml/min/g of tissue, and at the first experimental animal (the rat) 0,533. The throughput via the most superficial layers was 0,197 and 0,131. In the villus 1,04 x 10 on the minus 5, and 4,31 x 10 on the minus 6. Such strong reductions of flows through the most superficial layers caused also appropriate reaction of organisms. Conclusion: Vagotomy beside a strong reduction and redistribution of circulation guards elementary functions of intestinal uvulas. Similar changes were also in the jejunal mucosa. Lengths of villuses were reduced with 579,18 on 490,20 µm (15,36 %). The diameter of villuses were increased with 128,65 on 142,28 µm, and of CL with l3,94 on 17,10 µm. Radius a-v "b-p"on the top reduced with 5,41 on 3,53 µm (34,75 %), capillaries with 1,98 on 1,40 µm (29,29 %), CA with 3,82 on 1,83 (52,09 %), CV with 5,05 on 2,60 (51,49 %), MA with 2,23 on 1,76 (21,08 %), a-v "b-p” in the middle with 2,97 on 2,34 (21,21 %). Radius a-v "b-p" in the region of crypts reduced with 8,94 the mm in the third minute after vagotomy on 8,34 µm in tenth, what is a result more strongly reduction of circulation through all layers. SR of CA of jejunalnog vilusa grows, towards the condition before the vagotomy, for 150,3 times, CV for 95,97 times, "b-p" on top for 7,l8 times, "b-p" in the middle 65,69 times, MA for 91,31 times, capillaries 55,97 times. Changes of SR suggest keeping back the blood in capillaries and "b-p"-es on the top of villusses. There was reduced also the throughput of pre-mucous parts. Because of the strong contraction of smooth musculature was reduced the total volume of the intestine. 20 minutes after vagotomy changes of tested elements of circulation of the duodenal mucosa suggest additional reduction of circulation. Radius "b-p" on the top of villuses was 3,59 µm (before vagotomy 5,41, in 10 minutes after 3,53), CA 1,54 (3,82 and 1,83), CV 2,5l (5,05 and 2,66), capillares 1,44 (1,98 and 1,40), "b-p" in the middle 2,29 (2,97 and 2,25), MA 1,69 (2,23 and 1,76), "b-p" in the region of crypts 8,34 (0,1 and 7,59. There was changed also SR of tested segments of circulation. In the direction CA, "b-p" the top, CV (400,22 - 8,10 - 11,02) still ever we had relatively smaller resistance to the streaming of the blood through a-v anastomoses is than through CV. As SR MA 128,85, the blood was increasingly directed hereby and "b-p"-es in the middle of villuses whose SR was 68,91. The tops of villuses was contracted, and circulation reduced on the most basically functions. The strong reduction of circulation was found also in the jejunum. Radius a-v "b-p" on the top of villuses was 3,59 µm (5,41 and 3,53), CA 1,54 (3,82 and 1,83), CV 2,51 (5,05 and 2,66), capillary 1,44 (1,98 and 1,40), and-v " b-p " in the middle 2,29 (2,97 and 2,34), MA 1,69 {2,23 and 1,76). Beside tendency of returning some elements of circulation towards normal (gradually giving in spasms of the smooth musculature) the total throughput was still strongly reduced, the top of villuses were contracted, and circulation reduced on minimum. This was best seen from relative SR of tested segments of circulation. Sudden fall of SR in "b-p"-es in the middle of villuses enabled the fast flow of the reduced amounts of blood through main blood vessels with relatively better-preserved circulation of capillary areas. The throughput was still ever strongly reduced; radiuses CA and MA were still ever progressively reducing. 30 minutes after vagotomy circulation through mucosa of duodenum and jejunums was still ever strongly reduced, beside tendency for returning to normal. Radius of CA duodenal vilusa was 1,69 (3,40 and the l.,55), CV 2,59 (4,78 and 2,65), MA 1,53 (2,15 and 1,67), and-v "b-p" on top 3,93 (5,31 and 4,2l), "b-p" in the middle 1,95 (2,90 and 2,ll), and-v "b-p" of the region of crypts 7,01 (0,0l and 7,67). SR CA of duodenal villuses were 14236,65 (6.88 and 400,22), CV 257,27 (1,47 and the LL,02) "b-p" on the top of villuses 41,13 (0,34 and 8,10), "b-p" in the middle 5306,02 (4,83 1 68,91), MA 195,43 (5,68 and 8,10), "b-p" in the middle 5306,02 (4,83 and 68,91), MA 195,43 (5,68 and 128,45) and capillaries 2266,46 (4,53 and 98,63). Average values neither here were, as earlier at "b-p" in the middle of villuses in 10th minutes after vagotomy, reflection of a real situation. At one number of experimental animals circulation was hurriedly returning to normal (In the fifths and the ninth experimental animals were 1,l1 and 1,0l ml/min/g of tissue with still ever strong reduction of circulation in the region of villuses (the most superficial layers). In six experimental animals still ever there were a progressive reduction of circulation, while in others two was noticed a mild growth towards the condition in twentieth minute after vagotomy. SR "b-p"-es in the region of crypts were only 0,6. Radius of CA jejunal villuses were 1,97 (3,82 and 1,54), CV 3,45 (5,05 and 2,51) MA 1,88 (2,23 and 1,69}, a-v "b-p"-es on the top 5.38 (5,41 and 3,59), a-v "b-p" in the middle 2,48 (2,97 and 2,29), a-v "b-p" in the region of crypts 9,72 (0,01 and 8,34). SR of tested segments of circulation of jejunal villuses were pointed at gradually returning the circulation on the condition before vagotomy, beside still a strong reduction of circulation through the most superficially layers. SR CA were 64,52 (5,19 and 563,13), CV 6,68 (1,0 and 78,31), "b-p"-es on the top (0,33 and 2,7), capillaries 24,73 (6,19 and 57,78), "b-p" in the middle 3,47 (1,63 and 30,86), MA 97,30 (12,38 and 69,10) and "b-p"-es in the region of crypts 0,l7. 45 minutes after vagotomy, contraction of the smooth musculatures of duodenal villuses yields. Jejunal villus was contrary of it strongly contracted. The mucous throughput of duodenum was 0,742 ml/min/g of tissue, and jejunums 0,710. SR CA of duodenal villuses were 340,67 (6,88 and l4236,65), CV 69,56 (1,47 and 257,27), "b-p" above 1,09 (0,34 and 41,13), capillary 24,19 (4,53 and 2266,46), "b-p" in the middle 12,48 (4,83 and 5306,02), MA 26,48 (5,68 and 195,43), "b-p" crypts 2,99 (0,6 in the thirtieth minute after vagotomy). Radiuses CA were 1,83 (3,40 and 1,69), CV 2,74 (4,78 and 2,59), "b-p"-es at the top 4,35 (5,31 and 3,93), capillaries 1,36 (2,05 and 1,2l), "b-p"-es in the middle 2,21 (1,95 and 2,90), MA 1,62 (2,l5 and 1,53) and "b-p"-es in the region of crypts 8,42 (7,01 in the thirtieth minutes after vagotomy). Similar changes happened also in the jejunal mucosa. Radiuses CA were 4,07 (3,82 and 1,97), CV 3,23 (5,05 and 3,45), "b-p" on the top 4,93 (5,41 and 5,38), capillaries 1,59 (1,98 and 1,48), "b-p the" in the middle of villuses 2,32 (2,97 and 2,48), MA l.,82 (2,23 and the l.,88) and "b-p" in the region of crypts 7,8 (0,01 and 9,72). SR CA were 106,94 (5,l9 and 64,52), CV 12,79 (1,0 and 6,68), "b-p" on the top 10,61 (0,33 and 0,55), capillaries l4,92 (6,19 and 24,73), "b-p" in the middle of villuses 5,04 (1,63 and 3,47, MA 8,65 (97,13 and]2,38), "b-p" in the region of crypts 0,05 (0,17). Beside smaller oscillations the trend of returning to the condition before vagotomy was continuing. But, in spite of it the total flow was still strong reduced. 60 minutes after vagotomy the mucous throughput of duodenum was 0,812 (1,18 and 0742), from that through the region of crypts 0,463, and through the region of villuses 0,344 ml/min/g of tissue. Radius CA were 1,85 µm, CV 3,07 µm, "b-p" on the top 4,10 µm, capillaries 1,43 µm, "b-p" in the middle of villuses 2,l6 µm and MA 1,75 µm. SR CA were 384,73, CV 4,99, "b-p" on the top l.,08, capillaries 38,84, "b-p" in the middle 5,57, MA l0,l4 and "b-p" in the region of crypts 0,12. By oscillatory returning the normal circulation was increasingly faster repairing in the region of crypts than in the region of villuses (most superficial layers). Similar changes were found in the jejunal mucosa too. 90 minutes after vagotomy, circulation was farther reducing: in the duodenum on 0,652 ml/min/g, and in the jejunum on 0,676 ml/min/g. This pointed at slow returning to normal, perhaps days long! Initial post-vagotomic reactions of the mucous membranes of duodenum and jejunum were examined in the first minute after vagotomy in 10 experimental animals. It was recorded the initially decrease of volume of the villuses because of contraction of the smooth musculature. This is importantly because volumes of villuses, in the period of the largest reduction of flow in 3, 10, 20 and 30 minutes after vagotomy were increased (in duodenum) or minimally reduces (in jejunum). A decrease of volumes of villuses was happening, namely, later in 45, 60 and 90 minutes after vagotomy, when circulation was recovering. It was noticed diminishing of radiuses of all tested elements of circulation. So radiuses CA of the duodenal villuses were average 2,65 µm (before vagotomy 3,40), CV 4,13 (4,78), "b-p" on the top 4,41 (5,31), capillaries 1,69 (2,05), "b-p" in the middle 2,55 (2,90), MA 2,02 (2,15). "B-p"-es in the region of crypts were widen opened and theirs radiuses were 6,70 µm. Only radius "b-p" on the tops were slightly increased, what was a result of simultaneous contracting CA and CV. Presented results are arithmetic middle values of tested segments of circulation all experimental animals. They, however, do not give a correct display of the initial reaction. During analysis of the verisimilitudes of reductions of circulation, we found that in the first minute after vagotomy in the duodenum they were 0,7, and in the jejunum 0,6, while is total P l,0. In the first minute on the vagotomy in 3 cases in 10th minute after vagotomy in duodenum was not obtained expected reduction of circulation. In the jejunum this was happened in 4 animals. Reaction is not, therefore, probable and obligatory. Results demand the statistical processing. Probability as a measures of coincidences (the chance of appearing), will present us to dichotomy of measured characteristics. P CA CV b-p top capilaries b-p middle MA b-p crypt D 0,7 0,6 0,7 0,8 0,8 0,5 0,7 J 0,8 0,6 0,5 0,7 0,4 0,6 1,0 _____________________________________________________________ 0,75 0,6 0,6 0,75 0,6 0,55 0,85 From obtained values is visibly the order of contractions of tested segments of circulation, and with it also reductions of it, which are disharmonious. The first were contracted CA and capillaries, then CV, "b-p"-es on the top and "b-p"-es in the middle. Circulation in the region of crypts was intensified, as well as in basal parts of villuses (MA and "b-p"-es in the region of crypts). Reduction of circulation appeared in 7 cases in duodenum and in 6 in jejunum (P 0,7 and 0,6). But, in spite of it total P is 1. The strong reduction of circulation was achieved, namely, only in the third minute after vagotomy. Influence of a hypoxia on the post vagotomic circulation of duodenal and jejunal mucous membranes, and vice versa, was examined in four experimental animals (B, C, D and E). Hypoxia achieved with the passage of the vascular network with gelatin of the same viscosity with blood during several minutes. Samples of the mucous membrane was taken from 10 to 30 minutes after vagotomy. In the hypoxic intestine was confirmed a contractile post-vagotomic reaction of smooth musculature of villuses and blood vessels. In the previous shown series of 10 experimental animals was achieves the largest decrease of radiuses CA of 54,4l % in duodenum and 59,69 % in jejunum. Radiuses of CA of hypoxic duodenum were reduced for 70,59 %, and jejunum for 53,66 %. In accordance with it were changed SR of blood vessels and the throughput. The maximally decrease of the throughput in duodenum was 56,69 %, what is 0,511 ml/min/g of tissue. The throughput through the region of crypts was reduced, at the same time, for 38,32 %, and in the region of villuses for 81,69 %. In the previous series of 10 experimental animals the throughput was 0,628 mil/min/g of tissue (decrease 46,74 %), while the throughput through the region of crypts was 0,424 mil/min/g (decrease l8,57 %), and through the region of villuses 0,l86 mil/min/g (decrease 71,95 %). The maximally decrease of the throughput of the hypoxic jejunum was 45,93 % (0,638 mil/min/g). The throughput through the region of crypts, at the same time, was decreased for 54,07 % and was out 0,414 mil/min/g of tissue, and through the region of villuses 68,53% and was 0,208 mil/min/g. In the previous series of 10 experimental animals results were: 0,627, 0,418 and 0,190 ml/min/g in third minute and 0,659, 0,416 and 0,227 in the twentieth minute after vagotomy. Decrease in percentages in the third minute after vagotomy was 46,98 %, 19,67 % and 71,l9 %, and in the twentieth 44,28, 21,67 and 65,60 %. Hypothetical reductions of the throughput came in both series, in all 14 experimental animals. (P = 1) Conclusion: A moderated hypoxia does not change significantly post-vagotomic reaction of blood vessels. Influence of a hypercapnia on the post-vagotomic reaction of blood vessels of duodenum and jejunums was examined in two experimental animals. There was used the device for the extracorporeal circulation. Hypercapnia was achieved with passage of gelatin of the same viscosity with blood during 15 to 20 minutes. Radius CA of the duodenal villuses increased for 81,47 %, and the total mucous throughput for 139,83 %. Radius CA of the jejunal villuses increased for ll5,97 %, and the throughput for 88,14 %. The mucous throughput of duodenum was 2,83 mil/min/g and jejunum 2,22 ml/min/g. Conclusion: In hypercapnia post vagotomic contracted blood vessels of the mucous membranes of duodenum and jejunum became wider, and the total throughput through duodenum and jejunum increased. Cause for it is likely a paralysis of vasomotor nerves. IV. DISCUSSION Post-vagotomic contractile reactions of mucoses of duodenum and jejunum were caused by contraction of the muscular threads. Because of it, villuses became smaller and fatter, in the total volume smaller. Spaces among villuses became widened, openings of crypts larger. Mikrovili of endocrine cells of GEP system more easily receive information from the lumen on based of which they discharge theirs granules in peri-capillary spaces of the sub-epithelial capillary layer, mostly basal parts of villuses and the region of crypts. In this way, indirectly, these cells post-vagotomic influence on the mucous circulation. But, it is not the subject of this work. There was also eased emptying of Brunner glands. (Vagotomy reduces total secretion of all glands.) Contraction breadthways helps the network of elastic fibers, which penetrate in villuses and in the area of crypts directly from smooth muscular fibers. With contraction of the smooth musculature contract also the network of these fibers, and so abridge the region of crypts and villuses longwise and breadthways. The smooth musculature of the mucosa layer has two layers, inside mostly circular and outer mostly longitudinal. We said that a-v anastomose on the top of villuses important for the heart functioning, because in a non digestive phase blood directly, over this anastomose goes in veins, not spending energy for pushing blood through capillaries. For the heart are important also all others anastomoses, which after vagotomy redistribute blood from superficial in deeper layers. Important are also cells of GEP system, which over MA and sub-epithelial capillary layer of basal parts of villuses influence on circulation of a-v connections in the middle of villuses. . Maximal contractions of the smooth muscular fibers of the mucous membrane shrinks and shortens the top of villuses contracting "b-p"-es on the top with a pressure from outside. Through the region of crypts passes large central arterioles of villuses, which start from sub-mucous veins, penetrate the muscu1aris mucosa, enter in the region of crypts, and go parallel with central hiluses towards the top of villuses without branching. That we also said for smaller branches of sub-mucous arteries, which after penetrating the muskularis mucosa, enter in this region. From them emerge MA and the sub-epithelial capillary layer of the region of crypts. Before of vagotomy blood streams through these vessels passing by a-v anastomoses this region. Opening and exists anastomoses is visibly also in microscopic preparations obtained 3, 10, 20, 30, 45, 60 and 90 minutes after vagotomy. For a correct differentiating of these connections is necessary additional investigating. Vagotomy influences also on the lymph circulation of the mucous membrane of the small intestine. We already said that absorbed liquid gathers in the interstitial tissue, and that from here go away via blood and lymph capillaries. The hydrostatic and the oncotic pressures determine quantity of taken away liquid with every of these two systems. With accumulation of liquid grows the interstitial volume and the hydrostatic pressure, while the onkotski pressure falls. How the interstitial tissue is composed from collagens’ fibers and mucopolysaccharides, which are mutually interwoven in the gelatinous structure, hydraulic conductivity of normally hydrated interstitial tissue is very small. How the volume conductivity is vice versa proportional to the concentration of the chialuronic acid, the grows of the volume of liquid increases the hydraulic conductivity of the intestinal tissue. The oncotic pressure of the interstitial liquid falls. Also stops the capillary filtration. Filterable capillaries turn into absorptive. Lymph vessels fill also with liquid. Divisions of the mucous interstitial volume on central and the juxtacapilary parts ensures the passive flow of liquid in capillaries. The hydrostatic pressure is in juxtacapillaries’ areas more sensitive at changes of the volume of that in central interstitial spaces. Therefore a larger part of absorbed liquid takes away hereby. By an accumulation of liquid the largest part of the fall of oncotic pressure is visible just in that fragmentary sub-epithelial-juxtacapillary layer. By post-vagotomic contraction of the smooth musculature of villuses and blood vessels, grow the hydrostatic pressure, and become faster the passive flow of liquid in blood and lymph capillaries; grows also the colloidal-osmotic pressure of the interstitial fluid and concentration of the hyaluronic acid. Secretive capillaries become absorptive. Because of it, the contractive reaction of capillaries is less prompt from others segments of circulation. Larger part of liquid is taken away hereby directly in circulation. When colloidal-osmotic pressure grows, grows also concentration of the hyaluronic acid. The hydraulic conductivity falls, and liquid passively no longer penetrates in lymph vessels. The hydrostatic pressure pushes remaining liquid in the blood vessels. Because of the contraction of pre-capillary arterioles, the pressure in capillaries falls. It would be interesting to examine the role of GEP cells on circulation after vagotomy. Some gastro-intestinal hormones (cholecystokinin and the secretin) increase the intestinal flow of blood and lymph if they are instilled in a. mesenterica crania1is. Turner and Barrowman suggest that hormones exude during absorptions cause vascular changes (increased capillary perfusion and capillary pressure). The absorbed liquid increases the capillary’s hydrostatic pressure. As the hydraulic conductivity of the intestinal tissue reduced, because of considerable increase of concentration of the hyaluronic acid and increased the oncotic pressure, the capillary filling of sub-epithelial capillary’s layer increasingly carry's out with absorption of liquid from the intestinal lumen, and all more less from interstitial tissue. Organism compensates weaker perfusion with increased absorption of capillaries. In an absorptive phase of animals, which are not subjected to vagotomy, absorbed liquid spreads the interstitial space, grows the interstitial hydrostatic pressure and reduces oncotic. Changes cause flow of liquid from interstitial tissue in blood. After vagotomy the interstitial space becomes narrower and the hydrostatic and the oncotic pressures grow; increases also concentrations of the hyaluronic acid, and pre-capillary arterioles contract. The oncotic pressure in capillaries falls, because of absorption of liquid. In later phase increasingly less liquids is absorbed from interstitial tissue, more, and more, from the sub-epithelial juxta-capillary lymph space, immediately after absorption from the intestine. Weaker contractions of capillaries can be explained with the role of sympathicus. In the introduction we said that noradrenergic fibers go next to blood vessels and that are, especially well nerved the muskularis mucosa and the sub-mucosa. Dense solar plexuses surround blood vessels, especially in the region of crypts and in the sub-epithelial capillary layer of villuses and base-lateral membrane. The final sympathetic fibers of these plexuses terminate in capillaries. Contraction seems to be directly proportional to mass of the smooth musculature of appropriate segment of circulation. It seems that all is regulated so. Sympathicus plays the crucial role in the protection of the absorbed function of the intestine after vagotomy. Relatively weak the smooth musculatures of capillary veins make easier this function. Levens and coworkers think that alpha-receptors on the base-lateral membrane of epithelial cells bind noradrenalin on nerve final threads and accelerate transport of fluid. Wit this role of sympathicus is able interpret also relative slower and weaker contraction, not just capillaries, than also connections of these with varicosities nearby base-lateral membranes. Vagotomy, as well as stimulation of noradrenergic fibers of villuses, reduces lymph flow, coefficient of the capillary filtrations and pressure. It also reduces the pressure of the interstitial circulations and there is no so called "self-regulation". It was said that stimulation of sympathetic fibers of the small intestine promptly reduces the blood throughput, which after it gradually gives back in normal values. Vagotomy, on the other hand, initially, promptly poorly reduces the blood throughput. We can freely to say that it makes it something slower and initial oscillatory. Reaction is the strongest in the first 30 minutes after vagotomy. Actively are contracting arterioles and venulas and it balanced, arterioles something weaker of venulas. Because of this biphasic answer on a vagotomy, the capillary pressure does not depreciate considerably. Beside this rapid fall of the intestinal mucous throughput, capillaries are still ever weaker contracted of arterioles and venulas. However, they are in this phase still ever secretive although gradually grow their absorptive function. After adrenergic stimulation the intestinal throughput inside the first 5 minutes falls on 48,3 % with oscillations about 7 %, in order later be increased on 73,7 % with oscillations of 4,2 %. Coefficient of the capillary filtration of the adrenergic stimulated intestinal tissue is reduced on 75 % (later 25 %). After vagotomy reduction of the intestinal throughput, specially mucosal, is stronger. 10 minutes after vagotomy radius CA is 1,48 µm in the duodenum and 1,83 µm in the jejunum; 20 minutes after is 1,55 and 1,54; 30 minutes after is 1,69 and 1,97; 45 minutes is 1,83 and 2,07. In 60 minutes is 1,85 and 2,5. SR of CA of the duodenum grows with 6,88 before the vagotomy on 198,93 in the third minutes; 284,66 in tenth, 400,22 in twentieth and 14236,65 in thirtieth, when suddenly reduces that in 45 minutes is only 340,57. In the 60th minutes is again something bigger and is 384,73, and in ninetieth falls on 83,62. In the jejunum we have an increase from 5,19 before vagotomy on 243,68 in the third minute and 758,86 in tenth. In twentieth minute SR is 563,13, in thirtieth 64,52. In the 45th minute SR of CA of jejunal villuses is 106,94, in sixtieth 26,46, and in ninetieth 79,22. At SR we have also a oscillatory returning to normal. SR of CV grows more slowly, and of "b-p" on top lesser than of CA and CV. (See tables of arithmetic midpoints!). The total interstitial resistance grows mostly at account of pre-capillary resistance, as well as the venous segmental resistance. Biphasic answer becomes increasingly significant. Hereinto needs still ones look back at circulation in the region of crypts and the existence of numerous a-v connections in this area, which earlier are not described. Before a vagotomy a-v "b-p"-es of the region of crypts is not possible to notice, because they are contracted. 3, 10, 20, 30, 45, 60 and 90 minutes after vagotomy "b-p"-es of this region are dilated and the throughput is directed hereby by the most superficial layers of the duodenal and jejunal mucosa. The theoretical model of the vascular network of mucosa of the small intestine, which in 1979 years made Lewite and coworkers, do not mention a-v "b-p"-es in the region of crypts. Neither others authors notice anywhere importance of these anastomoses, which only post-vagotomic become visible. Thanking to them the vascular network of regions of crypts and villuses make one functional totality - vice versa of what so far was thinking. Lewite and coworkers are, namely, with injecting of the vascular network of the small intestine of rabbits with silicone’s foam and polystyrene’s micro-granules proved an independence of the blood throughput in the area of crypts from the throughput through villuses, what was completely understandable because those are two areas with different functions. With analysis of ours, microscopic preparations was visibly that it is correctly only in conditions in which the adrenergic system is not irritated, more precisely said, before vagotomy. In fact, after vagotomy circulation in the region of crypts and villuses is unique. A-v "b-p"-es in the region of crypts are turning aside the throughput by villuses. The biggest fall of the mukoznog throughput is noticing between tenth and thirtieth minutes after vagotomy. Vagotomy redistributes the throughput in the direction of the regions of crypts. From a special interest is analyses of the throughput in segments: capillaries, MA, and "b-p" in the middle of villuses. Contraction of capillaries lags after contraction of CA, CV and "b-p"-es on the top. Similarly is also with MA and "b-p"-es in the middle of villuses. Vagotomy guards the absorption function of the small intestine. Most poorly are contracted, and most quickly give back to normal "b -p"-es in the middle of villuses with which absorbed liquid directly takes away in the blood vessels. The throughput through the basal parts of villuses is relatively less reduced of that in apical parts. Wit analysis of SR of these vessels we get still better insight in reduction and redistribution of the throughput, as well as in the role of "b-p"-es in the middle of villuses. (See tables of arithmetic midpoints!) After vagotomy organism guards the most superficially layers from dehydration, maximally decreasing, simultaneously, circulation of them. V. CONCLUSION Vagotomy causes contraction of the smooth musculature of the intestine and reduces total the mucous and the pre-mucous throughput. Reduction is less prompt than after a sympathetic stimulation. The biggest decrease of the throughput achieves between 10th and 20th minutes after vagotomy, after it follows an oscillatory returning to normal, which lasts several hours, perhaps even weeks or months. With redistribution of the throughput, the blood is directed via the region of crypts. The biggest reduction of the throughput is in the most superficial layers (the region of villuses). The total mucous throughput reduces from 46,74 % in the duodenum on 46,98 % in the jejunum. Reduction of the throughput through the region of crypts is 20,92 % in the duodenum and 21,67 % in the jejunum. The throughput through the region of villuses reduces for 71,95 % in the duodenum and 71,19 % in the jejunum. With vagotomy is probably, in certain cases, to stop bleeding from the superficial layers of the mucosa of duodenum and jejunum. VI. COMPENDIUM - SUMMARY 1. In 10 experimental animals were examined the vascular answer of the duodenal and the jejunal mucous membranes 3, 10, 20, 30, 45, 60 and 90 minutes after vagotomy. 2. In 4 rabbits was examined the vascular answer the hypoxic duodenal and jejunal mucous membranes after vagotomy. 3. In 10 experimental animals were examined the initial post-vagotomic reaction of the duodenal and jejunal mucous membranes. 4. In 2 rabbits was examined the influence of vagotomy on the presence of a hypercapnia in the duodenal and the jejunal mucous membranes. The segmental resistance of the vascular network is calculated by help of Poiseuille' law. Lengths and widths of villuses and radiuses of CL and others tested segments of circulation are measured under the microscope, analyzing 50 typical examples in the every sample. The total mucous throughput is got as a relationship towards Lewit’s rabbit. In the same way is calculated the redistribution of the throughput between the region of crypts and villuses. The hypoxic and the hypercapnic circulation is studied with use a device for the extracorporeal circulation and passage an isolated winding of the intestine with to the gelatin that is of the same viscosity with the blood. It is confirmed the hypothesis of the work: Vagotomy also reduces the mucous throughput of the duodenum and the jujunum. The biggest decrease was achieved between third and twentieth minutes after vagotomy, and it for 46,74 % in the duodenum and 46,98 % in the jejunum (in the hypocsic winding 56,69 and 45,93 %). The throughput through the region of crypts decreased for 20,92 % in the duodenum and 2l,67 % in the jejunum (in hypoxia 38,32 and 54,07); in the region of villuses for 71,95 % in the duodenum and 71,19 % in the jejunum (in hypoxia 81,69 and 68,53 %). After 30 minutes follows an oscillatory returning to normal. Vagotomy is not in condition to reduce vasodilatation in hypercapnia. The total mucous throughput of a hypercapnic mucose after a vagotomy was increased for 139,83 % in the duodenum and 88,14 % in the jejunum. There were described a-v anastomoses in the region of crypts. It was proved that is the post-vagotomic circulations of the region of crypts and villuses unique. The order and promptness of studied changes indicates that the post-vagotomic reactions dependent of mass of the smooth musculatures. Contractive reaction is directly proportional to mass of the smooth musculatures. Dissertation was made in the Departments for the Physiology, the Histology and the Pharmacology of the Faculty of Medicine in Zagreb, the Department for the Pathology of the Military hospital Zagreb, and in the Administrative and Technical Service of the Self-governing Interesting Community of the health care and the health insurance of the municipality of the Long Village (Dugo Selo). Manager of work: Prof. dr. sc. Mladen Stulhofer VIII. LITERATURE 1. Nylader, G., Olerud S.: A simple micro-angiographic procedure for studying of the vascular patterns in the alimentary canal. Acta Soc. Med. Upsal., 1960, 65:374. 2. Nylader, G., Olerud, S.: The vascular pattern of the gastric mucosa of the rat, following vagotomy. Surg., Gynec., Obst., l12:457-480, 1961. 3. Spanner, R.: Neue befunde über die Blutwege der Darmwand und ihre functionelle Bedeutung. Morphol Jakob., 69:394, 1932. 4. Bell, P.R.F., Batersby, C.: Effect of Vagotomy on Gastric Mucosa Blood Flow. Gastroenterology, 54 (6):1037, 1968. 5. Peter, E.T., Nicoloff D.M., Sosin, H:., Walder, A.I., Wangensteen, O.H.: Relationship between gastric blood flow and secretion. Fed. Proc., 21:264, 1962. 6. Peter, E.T., Nicoloff, D.M., Leonard, A.S., Walder, A.I., Wangensteen, O.H.: Effect of vagal and sympathetic stimulation and ablation on gastric blood flow. JAMA, 183:1003, 1963. 7. Leonard, A.S., Long, D.M., Thomas of F., Walder, A.I., Peter, E,T., Wangensteen, O.H.: Hypothalamic influences on gastric mesenteric blood flow. Surg. Forum, 13:280, 1962. 8. Sullivan, R.C., Rutherford, R.B.., Wadel, W.R.: Surgical management of hemorrhagic the gastritis by vagotomy and pyloroplasty. Ann. Surg., 159:554,1964. 9. Duancic, V.: Basis of histology of man. The medical book Belgrade-Zagreb, 1983. 10. Teodorovic, J., Jereb, B.: Gastroeoterology, handbook, 149-150. “MONOS” Belgrade, 1976. 11. Jacobson, L.F., Noer, R.J.: The vascular pattern of the intestinal wall in various laboratory animals and man. Anat. Rec. 114:85-101, 1952. 12. Lewit, D.G. et al.: Model for mucosal circulation of rabbit’s small intestine. Am. J. Physio1., 1979 Oct., 237 (4):E 373-82. 13. Granger, D.N.,: Intestinal microcirculation and transmucosal fluid transport,. Am. J. Physiol., l98l. May, 240 (5):G 343-9 (30 ref). 14. Granger, D.N. et al.: Intestinal blood flow. Gastroenterology, 1980 APR., 78 (4):837-63 (316 ref). 15. Thomas, E.M. et al.: Sympathetic innervation of the jejunal villus. Acta Histochem. (Yens) 1983, 72 (1):85-9. 16. Shepherd, A.P.: Autoregulatory escape yen the gut: and systems analysis. Gastroenterology, 65:77-91, 1973. 17. Granger, D.N. et al.: Sympathetic stimulation and intestinal capillary fluid exchange. Am. J. Physiol., 1984 Sep., 247 (3 PT 1):G 279-83. 18. Brunssen, I., et a1.:The effect of vasodilatation and sympathetic nerves activation on net water absorption in the cat’s small intestine. Acta Physio1. Scand., 106:61-68. 1979. 19. Folkow, B.D.., et al: The effect of graded vasoconstrictor fibres stimulation on the intestinal resistance and capacitance vessels. Acta Physiol. Scand.: 6 1:445-457, 1964. 20. Lundgren, O.: Role of splanchnic resistance vessels in overall cardiovascular homeostasis. Federation Proc. 42:1673-1677, 1983. 21. Greenway, C.V.: Neural control and autoregulatory escape. In: Physiology of the Intestinal Circulation, edited by A.P. Shepherd and D.N. Granger. New York: Rhubarb, 1984, chapt. 5 p 61-71. 22. Lundgren, O., et al.: The effect of sympathetic vasoconstrictors’ fibers on the distribution of capillary flow in the intestine. Acta Physiol. Scand.: 61:458-466, 1964. 23. Shepherd, A.P.: Intestinal 0-2 uptake during sympathetic stimulation and partial arterial occlusion. Am. J. Physiol. 236 (Heart. Circ. Physiol. 15):H 731-H 735, 1979. 24. Lundgren, O. et al.: The effect of splanchnic nerves stimulation he blood flow distribution, villous tissue osmolarity and the fluid and the electrolyte transport in the small intestine of the cat. Acta Physiol. Scand. 117:365, 1983. 25, Gidda, J..With. , et al.: Influence of vagus nerves on electrical activity of opposum small intestine. Am. J. Physiol., 1980. Nov., 239(51):G 406. 26. Lewit, D.G., et al.: Model for mucosal circulation of rabbit small intestine. Am. J. Physiol., 1979. Oct., 237(4): E 373-82. 27. Shepherd, A.P.: Intestinal capillary blood flow during metabolic hyperemia. Am. J. Physiol., 1979. Dec., 237(6): E 548-54. 28. Walder, D.N.: Arteriovenous anastomoses of the human stomach. Clin. Sc. 11:59, 1952. 29. Tani, N. et al.: Lesions of the upper gastrointestinal tract in patients with chronic renal failure. Gastroenterol. Jpn. 198O, 15(5):48O-4. 30. Dillard, R.G.: Fatal gastrointestinal hemorrhage in a neonate treated with tolazoline. Clin. Pediatr. (Phila) 1982. Dec., 21.(12):761-2. 31. Thorsen, J. et al.: Field trials of an immunization procedure against hemorrhagic enteritis of Turkey. Avian Dis. 1982. Jul. -Sep., 26(8):473-7. 32. Laosombat, V., et al.: Massive intestinal hemorrhage leading to exploratory laparatomy in child with hookworm infecton. Southest Asian J. Trop. Med. Public' Health 1980. Jun, 11(2):269-72. 33. Frank, D.J, et al.: Massive gastrointestinan bleeding in a patient with Recklinghausensens disease: case report. Milit. Med. 1981. Jun., 146(6):438-9. 34. Gerbal: J.L., et al.: Postoperative acute muco-erosive jejunoileitis with protein-loosing enteropathy: recovery after partial resection of the small intestine. Gastroeenterol. Clin. Biol., 1980. Dec., 4(12):881-7. 36. Gajo, R., et al.: Massive upper gastrointestinal bleeding. Data on 369 surgically treated patients. Am. J. Surg., 1980. Nov., l40(5):639-41. 37. Kiwerski, J.: Gastrointestinal hemorrhage during treatment of spinal cord injuries. Chir.. Narzadow Rucku Ortop. Pol. 1982. 47(4):275-9 ( Engl. abstr.) Pol. 38. Yoshihara, T. et al.: Gastrointestinal bleeding in patients with severe head injury, hypertensive intracerebral hemorrhage, and ruptured cerebral aneurysm. Hiroshima J. Med. Sci., 1983. Mar., 32(1):35-40. 39. El Masri, W.E. et al.: Gastrointestinal bleeding in patients with acute spinal. injuries. Injury, 1982. Sep., 14(2):162-7. 40. Wexler, R.M., et al.: Duodenal erosion of a Mesocaval graft; an unusual complication of mesocaval shunt interposition surgery. Gastroenterology, 1980. Oct. 79(4):729-30. 41. Tingaud, R. et al.: Digestive hemorrhage caused by seromuscular erosion of the wall of a section of the small intestine at the 1evel of an aortic prosthesis implanted 5 years earlier. J. Mal. Vase. 1982., 7(3):179-82 (Engl. Abstr.) fre. 42. Kacerowski-Bre1isz, G., et. a1.: Massive intestinal bleeding caused by yershinia pseudotuberculosis (author transl). Z. Gastroenterol., 1980., Jul, 18(7):372-5!11.:372-5, (Engl. Abstr.). 43. Barlow, T.E., Bentley, F.H., Walder, D.N.: Arteries, veins, and arteriovenous anastomoses in the human stomach. Surg. Gin. Obst., 93:657, 1951. blood flow and secretion. Fed. Proc., 21:264, 1962. 6. Peter, E.T., Nicoloff, D.M., Leonard, A.S., Walder, A.I., Wangensteen, O.H.: Effect of vagal and sympa¬thetic stimulation and ablation on gastric blood flow. JAMA, 183:1003, 1963. 7. Leonard, A.S., Long, D.M., Thomas F., Walder, A.I., Peter, E,T., Wangensteen, O.H.: Hypothalamic influ¬ences on gastric mesenteric blood flow. Surg. Forum, 13:280, 1962. 8. Sullivan, R.C., Rutherford, R.B.., Wadel, W.R.: Surgical management of hemorrhagic gastritis by vago¬tomy and pyloroplasty. Ann. Surg., 159:554,1964. 9. Duančić, V.: Osnove histologije čovjeka. Medicinska knjiga Beograd -Zagreb, 1983. 10. Teodorović, J., Jereb, B.: Gastroeoterologija, priručnik, str 149-150. “MONOS” Beograd, 1976. 11. Jacobson, L.F., Noer, R.J.: The vascular pattern of the intestinal wall in various laboratory animals aod man. Anat. Rec. 114:85-101, 1952. 12. Lewit, D.G. et al.: Model for mucosal circulation of rabbit small intestine. Am. J. Physio1., 1979. Oct., 237(4):E 373-82. 13. Granger, D.N.,: Intestinal microcirculation and transmucosal fluid transport,. Am. J. Physiol., l98l. May, 240(5):G 343-9 (30 ref). 14. Granger, D.N. et al.: Intestinal blood flow. Gastroenterology, 1980. Apr., 78(4):837-63 (316 ref). 15. Thomas, E.M. et al.: Sympathetic innervation of the jejunal villus. Acta Histochem. (Jena) 1983., 72(1):85-9 16. Shepherd, A.P.: Autoregulatory escape in the gut: a systems analysis. Gastroenterology, 65:77-91, 1973. 17. Granger, D.N. et al.: Sympathetic stimulation and intestinal capillary fluid exchange. Am. J. Physiol., 1984. Sep., 247(3 Pt 1):G 279-83. 18. Brunssen, I., et a1.: The effect of vasodilatation and sympathetic nerve activation on net water absorption in the cats small intestine. Acta Physio1. Scand., 106:61-68. 1979. 19. Folkow, B.D.., et al: The effect of graded vasoconstrictor fibre stimulation on the intestinal resi¬stance and capacitance vessels. Acta Physiol. Scand.: 6 1:445-457, 1964. 20. Lundgren, 0.: Role of splanchnic resistance vessels in overall cardiovascular homeostasis. Federation Proc. 42:1673-1677, 1983. 21. Greenway, C.V.: Neural control and autoregulatory escape. In: Physiology of the Intestinal Circulation, edited by A.P. Shepherd and D.N. Granger. New York: Raven, 1984, chapt. 5 p 61-71. 22. Lundgren, 0., et al.: The effect of sympathetic vaso¬onstrictor fibres on the distribution of capillary flow in the intestine. Acta Physiol. Scand.: 61:458-466, 1964. 23. Shepherd, A.P.: Intestinal 0-2 uptake during sympathetic stimulation aud partial arterial occlusion. Am. J. Physiol. 236 (Heart. Circ. Physiol. 15): H 731-H 735, 1979. 24. Lundgren, 0. et al.: The effect of splanchnic nerve stimulation on blood flow distribution, villous tissue¬ osmolarity and fluid and electrolyte transport in the small. intestine of the cat. Acta Physiol. Scand. 117:365, 1983. 25. Gidda, J..S. , et al.: Influence of vagus nerves on electrical activity of opposum small intestine. Am. J. Physiol., 1980. Nov., 239(51):G 406. 26. Lewit, D.G., et al.: Model for mucosal circulation of rabbit small intestine. Am. J. Physiol., 1979. Oct., 237(4): E 373-82. 27. Shepherd, A.P.: Intestinal capillary blood flow during metabolic hyperemia. Am. J. Physiol., 1979. Dec., 237(6): E 548-54. 28. Walder, D.N.: Arteriovenous anastomoses of the human stomach. Clin. Sc. 11:59, 1952. 29. Tani, N. et al.: Lesions of the upper gastrointestinal tract in patients with chronic renal failure. Gastroenterol. Jpn. 198O, 15(5):48O-4. 30. Dillard, R.G.: Fatal gastrointestinal hemorrhage in a neonate treated with tolazoline. Clin. Pediatr. (Phila) 1982. Dec., 21.(12):761-2. 31. Thorsen, J. et al.: Field trials of an immunization procedure against hemorrhagic enteritis of Turkey. Avian Dis. 1982. Jul. -Sep., 26(8):473-7. 32. Laosombat, V., et al.: Massive intestinal hemorrhage leading to exploratory laparatomy in child with hookworm infecton. Southest Asian J. Trop. Med. Public' Health 1980. Jun, 11(2):269-72. 33. Frank, D.J, et al.: Massive gastrointestinan bleeding in a patient with vou Recklinghausensens disease: case report. Milit. Med. 1981. Jun., 146(6):438-9. 34. Gerbal: J.L., et al.: Postoperative acute mucoerosive¬ jejunoileitis with protein-loosing enteropathy: recovery after partial resection of the small inte¬stine. Gastroeenterol. Clin. Biol., 1980. Dec., 4(12):881-7. 36. Gajo, R., et al.: Massive upper gastrointestinal bleeding. Data on 369 surgically treated patients. Am. J. Surg., 1980. Nov., l40(5):639-41. 37. Kiwerski, J.: Gastrointestinal hemorrhage during treatment of spinal cord injuries. Chir.. Narzadow Rucku Ortop. Pol. 1982. 47(4):275-9 ( Engl. abstr.) Pol. 38. Yoshihara, T. et al.: Gastrointestinal bleeding in patients with severe head injury, hypertensive intracerebral hemorrhage, and ruptured cerebral aneurysm. Hiroshima J. Med. Sci., 1983. Mar., 32(1):35-40. 39. El Masri, W.E. et al.: Gastrointestinal bleeding in patients with acute spinal. injuries. Injury, 1982. Sep., 14(2):162-7. 40. Wexler, R.M., et al.: Duodenal erosion of a Mesocaval graft; an unusual complication of mesocaval shunt interposition surgery. Gastroenterology, 1980. Oct. 79(4):729-30. 41. Tingaud, R. et al.: Digestive hemorrhage caused by seromuscular erosion of the wall of a section of the small intestine at the 1evel of an aortic prosthesis implanted 5 years earlier. J. Mal. Vase. 1982., 7(3):179-82 (Engl. Abstr.) fre. 42. Kacerowski-Bre1isz, G., et. a1.: Massive intestinal bleeding caused by yershinia pseudotuberculosis (author transl). Z. 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8,259,661,996,871,633,000 | What Is Red Cell Distribution Width on a Complete Blood Count?
What to expect when undergoing this test
Red cell distribution width (RDW) is one of the numbers or blood cell indices that is included as part of a complete blood count (CBC), and describes the variation in the size of red blood cells in a sample of blood. A higher RDW means that there is a greater variation in the size of red blood cells than expected. The RDW can be very helpful in distinguishing between the different types of anemia, especially if there is more than one type of anemia present.
Even when blood counts such as the red blood cell count are normal, however, the RDW can be a valuable test. For example, it can predict iron deficiency in pregnant women even before anemia occurs (iron deficiency increases the risk for both mothers and babies). It may also be helpful in estimating heart disease or cancer risk, and some physicians believe, may be a test that assesses overall well-being.
There are limitations in evaluating the RDW such as after a person has had a blood transfusion. RDW may also be referred to as erythrocyte distribution width or RDW-SD (standard deviation test).
Purpose of RDW Test
The red cell distribution width (RDW) is done as part of a CBC and is, therefore, a commonly performed test that is used both for screening healthy individuals and to evaluate a wide range of medical conditions.
There are times when physicians may specifically look at the value of RDW:
• with symptoms of anemia, such as lightheadedness or fatigue
• to help diagnose the causes of anemia (a wide variation in the size of cells or a high RDW may occur when more than one type of anemia is present)
• to screen people who have a history of a red blood cell condition such as thalassemia
• with heart disease (an elevated RDW is a strong predictor for eventual heart failure)
• to screen for early iron deficiency in pregnant women before anemia occurs
• to screen for early vitamin B12 and folate deficiency before other signs are noted in the blood
• to have an idea when further blood tests (peripheral smear) are needed
• as an adjunct in estimating disease risk (heart disease, cancer, and more) or defining prognosis
RDW Calculation
RDW may be reported as either standard deviation (SD) or coefficient of variation (CV), but RDW-CV is most common. One standard deviation of RBC volume divided by the MCV times 100.
• SD / MCV x 100
RDW Meaning
The RDW is used to describe the amount of variation in the size of red blood cells, with the term anisocytosis used to describe this variation. In other words, talking about significant anisocytosis on a blood smear would mean that the red blood cells vary significantly in size.
Red blood cells are usually fairly uniform in size, and an increase in variation or anisocytosis (an increased RDW) can mean several things. A high RDW can be a sign of some types of anemia as well as a general sign of inflammation in the body.
Limitations
If an RDW is drawn after a blood transfusion, it won't accurately reflect the RDW of a person's cells. If a lab uses EDTA anticoagulated blood instead of citrated blood, the reading will be falsely high. Since the RDW-CV is calculated using MCV, an error in MCV will result in an error in the RDW.
Similar Tests
Variation in red blood cell size may also be noted visually by looking at a peripheral smear for morphology, though this test is usually done after a CBC to investigate an abnormality.
Complementary Tests
Since the RDW is done as part of a CBC, the number is reported along with several other values and the combination of results is usually used rather than the RDW alone. These include the number of each type of the blood cells and other red blood cell indices.
• Red blood cells (RBCs)
• White blood cells (WBCs)
• Platelets
• Hemoglobin and hematocrit
• Mean corpuscular volume (MCV) or the measure of the size of red blood cells
• Mean corpuscular hemoglobin concentration (MCHC) or the measure of the concentration of hemoglobin in a specific volume of red blood cells
• Mean corpuscular hemoglobin (MCH), which parallels the MCV and has little value in general
• Mean platelet volume (MPV), which is the average volume of platelets that can provide clues about many diseases
Additional Tests
In addition to the CBC, other tests that may be ordered to evaluate anemia include a reticulocyte count, blood smear for morphology, iron studies, and more.
Risks and Contraindications
Since the RDW is part of a simple blood test, there are very few risks. Uncommonly people may experience bleeding at the puncture site, bruising (a hematoma), or infection.
Before The Test
There are no special dietary or activity restrictions prior to doing an RDW (CBC). You will need to have your insurance card and it's helpful to provide your doctor with any previous CBC results for comparison.
During the Test
A CBC may be drawn in the hospital as well as many clinics. Before drawing your blood, a lab technician will clean the area (usually an arm) with antiseptic and apply a tourniquet to make the vein easier to see. She will then insert the needle through your skin and into the vein. While the needle is inserted you may feel a sharp (but short) sting, and some people may experience lightheadedness or feel faint.
After the sample is removed, the needle is removed and pressure applied to the puncture wound. A dressing is then applied to keep the area clean and reduce any bleeding.
After the Test
As soon as your blood is drawn, you will be able to return home. Potential side effects may include:
• Bleeding. Sometimes the area where your blood was drawn will continue to bleed, though this is most common for those who are on blood thinners or have a bleeding disorder. Most often this can be resolved with applying pressure, but if bleeding persists you should contact your doctor.
• Hematoma. Uncommonly, a large bruise may develop where your blood was drawn. This, again, is more common for those who are taking blood thinners such as anti-platelet medications.
• Infection. There is a very small risk that an infection could develop as a result of bacteria on the skin being introduced into the body during the blood draw.
Interpreting Results
If your clinic has a lab associated with it, most often you will receive your results shortly after they are completed. In some cases, the blood sample will be sent out to a lab and your doctor will call with results when they are available.
When you receive your results, it's helpful to ask for the exact numbers, including that of your RDW. As discussed below, the RDW may give important information even of the remainder of tests on your CBC are normal.
Reference Range
Reference ranges for RDW can vary somewhat by the laboratory doing the test. Normal red blood cells average between 6 and 8 micrometers in diameter. RDW estimates the variation in sizes of the cells and is given as a percentage. The normal range for RDW is roughly 11.8 to 15.6 percent, and the number often increases with age.
Normal RDW with Anemia
Examples of anemias in which RDW is most often normal include:
• Thalassemia (some types)
• Anemia of chronic disease
• Liver disease
• Alcohol abuse anemia
• Aplastic anemia
High RDW
A few types of anemia associated with an elevated RDW include:
• Iron deficiency anemia including early deficiency
• Vitamin B12 and folate deficiency
• Mixed anemias
• Sickle cell disease
• Myelofibrosis
• Cold agglutinin disease
Using RDW and MCV Together
Using the combination of RDW and MCV is very helpful in differentiating some types of anemia which would otherwise be difficult to tell apart. For example, both iron deficiency anemia and thalassemia are usually associated with a low MCV (microcytic anemias), but the two conditions are treated differently. Checking the RDW can help distinguish between these.
Similarly, megaloblastic anemias (such as vitamin B12 deficiency and folate deficiency) and non-megaloblastic anemias (such as anemia related to liver disease) are both associated with a high MCV (macrocytic anemias), but again are treated differently. In this case, the megaloblastic anemias usually have a high RDW and non-megaloblastic a low RDW, helping to make the distinction.
RDW can also be very helpful in mixed anemias. For example, a combination of iron deficiency (microcytic anemia) and folate deficiency anemia (macrocytosis) may have a normal MCV (normocytic anemia), but the RDW will be very high.
The following are examples of what conditions that RDW and MCV rates may indicate. It's important to note that there are exceptions to these general rules—for example, sometimes anemia of chronic disease is associated with a low MCV, and sometimes iron deficiency anemia will show a normal MCV.
• High RDW and Low MCV: Iron deficiency anemia, sickle cell, beta-thalassemia, or hemoglobin H
• High RDW and Normal MCV: Early iron deficiency anemia, early B12/folate deficiency, blood loss (chronic), or hemolysis
• High RDW and High MCV: Vitamin B12 deficiency, folate deficiency, immune hemolytic anemia, or this is a prevalent combination in newborns
• Normal RDW and Low MCV: Anemia of chronic disease, thalassemia, hemoglobin E trait
• Normal RDW and Normal MCV: Blood loss (acute), anemia of kidney disease, some abnormal hemoglobins, or spherocytosis
• Normal RDW and High MCV: Aplastic anemia, liver disease, alcohol abuse, some medications result in this combination (such as chemotherapy or antivirals)
Other Tests
In addition to a CBC, other tests that may be done to help identify anemia include:
• Reticulocyte Count: The reticulocyte count helps separate anemias into those based on lack of production of red blood cells (normal reticulocyte count) and those in which there is a loss or break down of red blood cells (blood loss or hemolysis).
• Blood Smear: In a peripheral blood smear, the blood sample is viewed under the microscope. In addition to being able to visualize differences in size and shape, other findings may include target cells, nucleated red blood cells, fragmented red blood cells (with hemolysis), and more.
• Iron Studies: Serum iron and iron-binding capacity and/or serum ferritin can measure iron stores in the body.
• Vitamin B12: If vitamin B12 deficiency is suspected, a vitamin B12 level will be drawn.
• Hemoglobin Electrophoresis: This study can find some (but not all) types of thalassemia.
• Bone Marrow Study: A bone marrow aspiration and/or biopsy may be done to look at the types of cells in the bone marrow and iron stores.
Non-Anemia Uses for RDW
The RDW can be a very helpful number even if there is no evidence of anemia (if the red blood cell count and hemoglobin levels are normal).
The RDW can predict the overall risk of mortality in people over the age of 45 (people with a high RDW are more likely to die earlier on than those who have a lower RDW).
Many studies have been done in the last several years looking at the predictive value of RDW in a wide range of diseases. Some of these include
• Heart Disease: RDW appears to be a strong predictor of heart failure in people with heart disease, and also predicts the risk of heart disease developing in people with high blood pressure. A 2014 study found that people with a very high RDW (in the top 5 percent) were 71 percent more likely to have a heart attack than those who had a lower RDW. A high RDW may also help predict the risk of heart disease in people who are infected with HIV,
• Cancer: Studies have looked at the role of RDW in cancer in a few different ways. With several types of cancer (such as blood-related cancers, lung cancer, and colon cancer), a high RDW may signify a poorer prognosis.
From another angle, researchers have looked at the potential for RDW to predict the risk of cancer in people who do not currently have the disease. For example, they found a dose-dependent relationship between high RDW values in men and postmenopausal women and future cancer risk.
For people who are undergoing evaluation for unintentional weight loss, a high RDW increased the chance that the weight loss was due to cancer.
• Surgery: Studies looking at different types of surgery have found that RDW may predict the risk of complications after surgery, to the point where it was pointed out that RDW is important for orthopedic surgeons.
• Sleep: A high RDW is linked to some sleep disorders, such as sleep apnea, and is also elevated in those who get too little or too much sleep or do shift work.
• Diabetes: People who have elevated RDW appear to have a greater risk of developing diabetes.
This area of research (looking at the role of RDW in evaluating conditions other than blood conditions) is quite new, and it's expected that more information will be available to better understand the potential benefits of looking at RDW in the future.
• Inflammatory/Autoimmune Conditions: An increased RDW has been associated with a number of inflammatory and autoimmune conditions, ranging from lupus to autoimmune thyroiditis.
Follow-Up
Follow-up testing if the RDW is abnormal will depend on many factors. Be sure to discuss your results with your doctor and he/she should provide any follow up
A Word From Verywell
Red cell distribution width (RDW) is a valuable tool in evaluating the different types of anemia and may have a wide range of uses even when a person's red blood cell count is normal. In addition to the conditions mentioned above, some argue that RDW could be a measure of general well-being.
For now, it's uncertain the value this test will have in many conditions but it's noteworthy that simple tests such as these—that can easily be overlooked—may provide important information to be heeded.
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7,736,895,135,081,330,000 | Virility and Hair Loss: Are Bald Men More Virile or Does Low T Cause Hair Loss?
Simply Men's Health Boca Raton West Palm Beach RejuvaWAVE ED shockwave unclogs arteries and restores spontaneous sexual function
Despite the popular myth of bald men are sexier and have higher testosterone levels, this is not necessarily the case. Conversely, low testosterone does NOT cause hair loss in men.
Testosterone is a sex hormone that is important in both men and women
Testosterone, an androgen hormone, is responsible for sex drive, muscle development, male characteristics and overall health. Actually, testosterone levels vary throughout the day peaking in the morning and lowest at night. As a matter of fact, in healthy adult men, normal testosterone levels can range from around 240 to 950 ng/dl.
Myth: Testosterone supplements make men more virile
Contrary to widely spread belief, testosterone supplements make men more virile. Commonly you see men stocking up on Testosterone supplements at the health food store, online of getting bootleg testosterone at the gym to beef up. But, what men don’t realize is that while testosterone may make their muscles pop, it also makes their testicles shrivel up. As a result, all these 30-40 year old men supplementing testosterone pumping iron in the gym, end up destroying their fertility and virility.
Taking testosterone to bulk up in the gym causes the brain to sense adequate testosterone levels. Therefore, the brain signals the testicles to stop making their own testosterone. And finally, as a result your testicles shrivel up and eventually become non-functional.
Does high Testosterone or low Testosterone cause male pattern baldness?
Testosterone indirectly affects male pattern hair loss. But bald men are more virile is not necessarily true. Also, bald men do not necessarily have low testosterone. As a matter of fact, testosterone and male pattern baldness is only part of the story. Namely, the hormone dihydrotestosterone (DHT) is responsible for male pattern hair loss.
DHT is the hormone that causes male pattern hair loss, not testosterone.
DHT Testosterone Male Pattern Hair Loss Simply Men's Health Boca Raton Palm Beach
Dihydrotestosterone, a derivative of testosterone, causes hair loss in men genetically predisposed to male pattern hair loss. Unlike testosterone that is found throughout the body affecting many aspects of our health, DHT is only found in skin, hair follicles and in the prostate. An enzyme called 5- alpha reductase converts testosterone to DHT in men. Therefore, male pattern hair loss is not due to high or low levels of testosterone. Rather, in conclusion, what causes hair loss in men is the sensitivity of the hair follicle to DHT. Often, this sensitivity of the hair follicle to DHT is genetically determined. Furthermore, bald men are not more manly or virile.
The truth about male pattern hair loss and testosterone.
While testosterone is involved in male pattern baldness, it is not the actual level of testosterone (high or low), but rather it is how much DHT your body produces. And in addition, how sensitive your hair follicles are to the testosterone derivative, DHT. Consequently, since not all follicles are susceptible to DHT, a bald man can still grow a beard and have body hair.
Simply Men’s Health NON-Surgical Hair Restoration – REGROW your own hair! No surgery, No plugs, No transplants
Simply Men’s Health physicians specialize in hair loss regrowing hair in men for over twenty years. REGROW you own hair. No weaves, no hair pieces, no surgery, no plugs or transplants. Imagine regrowing a full of head of your own natural hair. Contact us at 561-232-3704 or visit our website at Simply Men’s Health. | {
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3,977,071,174,973,735,400 | Creating calm in the clinic
Most affected by the HIV epidemic face many stressors such as racism, homophobia, financial constraints, and stigma around drug use—all of which can lead to distress. Understanding that someone is distressed, rather than labeling them as “difficult,” is essential, says Mathew R. Roosa, LCSW-R. A negative label distracts from working well together to resolve challenges to a person’s health care.
“You’re trying to figure out how to continue providing care while managing a person’s distress within a limited amount of time and resources,” says Roosa. “How can we pivot to address the distress so we can get back to providing the care that is our primary goal?”
Roosa has worked on a number of research projects designed to enhance mental health support in HIV care settings. His clinical work includes serving as a mental health and substance use therapist, agency administrator, and government planner for mental health and substance use services. Now working as a consultant, Roosa helped put together a presentation, Creating Calm: Engaging People Who are Distressed, for the Mental Health Technology Transfer Center (MHTTC). He speaks here to key points for creating calm, why we need to avoid language such as “acting out,” and to the magic of empathy.
Mental health first aid for everyone
“We find that there is a lot of good training for clinical staff—social workers, psychologists, counselors, marriage and family therapists—for effective response to people who are having a lot of strong emotional dysregulation. By that we mean stressors that are creating intense emotional reactions that might be getting in the way of their functioning, causing them to struggle or not be able to think clearly or solve problems in the moment. There isn’t, however, so much stuff out there for individuals who are not working as a mental health clinician, such as people sitting at the front desk or coming in to do research surveys.
“There’s now this field of mental health first aid, which lets us know that there are core things that all of us can do to help someone who’s having a crisis or a strong emotional challenge. It’s like regular first aid. We can all apply some physical first aid now. We don’t need to be a nurse or a doctor.”
Pivoting
“We know what it’s like when someone’s really upset and we’re trying to just push them through the service. And they’re reluctant to do that because they’re upset. If we can just take a minute to do something else, we may be able to re-establish our connection and de-escalate their level of distress, and then we can more efficiently move back into that care.
“Rather than leaning in, try to lean back. Rather than asserting, try to ask questions. Try to provide an opportunity for the person to communicate with you, rather than you trying to dictate to the person. That’s hard when things are stressful, because we all want for things to get less stressful quickly. So we often engage in behaviors that inadvertently create more stress. Avoid that quick reaction and create some space for that person. They might be yelling or wagging their finger at us, but in fact what’s happening is that they’re worried. So much of a person’s distress can be managed if you’re sharing empathy and building trust.”
Don’t worry about opening a can of worms
“I’ve talked to a lot of providers and some very skilled, excellent ones who will say, ‘Gosh, I really don’t want to ask those questions because I don’t feel like I have the time, the staff, or the resources to respond.’ No one feels good about that. The challenge is to come up with some clear, simple strategies to respond effectively.” (See How to create calm while engaging with distressed people.) (insert link)
Speaking up
“I’ve seen it over and over that when someone becomes very upset, either because they’re angry, frustrated, worried, or concerned, there is a frequent tendency to ease that burden by telling the person what they should do, giving them specific directions, or telling them that they should try to calm down. It’s almost always well intentioned. And it almost never works, because we all know what it’s like when someone tells us to calm down when we’re feeling upset. We generally feel like our experience is being discredited, disrespected, or ignored, and we usually get more upset. It’s like, I’m being loud so that you can hear me. You’re telling me to calm down, which means you’re not hearing me, which means I need to get louder in order for you to hear me.”
Words matter
“Using the words ‘acting out’—that’s a tremendous judgment. I put you in a one down [lower] position, and I put myself in a position of judgment, power, and control. That is the opposite of what we want to do when we’re trying to help someone feel more in control and more able to make decisions. My belief about your behavior might determine how we understand and address the situation. ‘Acting out’ is terrible language and is also infantilizing because it is language that’s associated with children. And so when we use it in reference to adults, that’s another way that it’s stigmatizing and disrespectful.
‘Rather than leaning in, try to lean back. Rather than asserting, try to ask questions. Try to provide an opportunity for the person to communicate with you.’
“The language that we’re using here, in terms of creating calm for people who are distressed, is what I like to think of as a much more empathic and person-centered language. We see a lot of language related to ‘difficult’ or ‘challenging’ people. And those are versions of judgmental language which tend to distance us from empathy toward that individual. We are all difficult at times.”
Trauma-informed
“We traditionally used to think about trauma as a ‘yes or no’ question. You either experienced these things that were very difficult, which have resulted in some challenges for you currently, or you were able to resolve that trauma and so you’re not struggling with it currently. But we didn’t think of it as a universal phenomenon.
“The reality is that it’s more of a spectrum. Most everyone has some experiences from their earlier years that caused pain. They have a legacy in their current life that might impact how they see the world or how they react to stressful situations. So, rather than yes or no, it’s what is my history of trauma? How much did I experience? And how is it impacting me now?”
Cultural divide
“I had one training with several people where a trainer responded to two African American women sharing ideas with each other by saying, ‘Well, there’s no reason to get angry about it.’ The whole room fell apart. The women just had a slight disagreement with each other and were a little bit animated in their expression of their ideas. He was a white man who saw the discussion as a fight. We had to do all this damage control discussing this harsh judgment and this cross-cultural barrier. That’s a good example of a lack of empathy. He did not understand what they were thinking or feeling and he didn’t have a cultural lens that allowed him to understand them.”
Empathy is not tolerance
“There are times when people need to get kicked out. Someone comes in and tries to punch someone at the front desk, they should get arrested. We can’t tolerate that. At the end of the day, we have to keep people safe and healthy and able to deliver care and support. And if there’s exposure to that kind of hurt, they won’t be able to do it.
“I think it’s actually lacking in empathy when you tolerate problematic behaviors because then you allow that person to get further away from healthy behaviors. It allows them to get closer to high risk for themselves and for others. That’s not an empathic and compassionate response. We’re not expecting much of them. We’re not appreciating their humanity and their capacity to improve and move towards healthier behaviors. Healthy boundaries are part of an empathic compassionate response. ‘We want to have you aspire to healthy behavior and that is not what this is.’
“Concerns include anger and rage. Second-most common is anxiety and panic. Distrust and paranoia feed on each other. Distrust-related paranoia often can result in risks to safety because people feel like they’re being mistreated or that they’re at risk, or that someone’s trying to harm them. And so they might feel a need to protect themselves. That can create some pretty serious risks.
“Calling the cops, however, can cause great harm. We need to find alternatives to calling the police in some types of situations. Involving emergency services like the police is a last resort.”
Empathy, not sympathy
“Understanding empathy is maybe the most important part of all of this because most people don’t appreciate empathy for what it is. It is not sympathy. It is not a warm, fuzzy feeling sorry for someone.
“Empathy is more head than it is heart. Empathy is more about understanding what the person is experiencing, trying to put yourself in their shoes and appreciate what they’re thinking and feeling, and how that relates to what they’re doing. ‘Understanding’ is a better word to use when defining empathy.”
Also go to mentalhealthfirstaid.org. For copies of the Creating Calm for People Who are Distressed PowerPoint presentation, email greatlakes@MHTTCnetwork.org. MHTTC supports resource development and dissemination along with training and technical assistance for the mental health field. In addition to regional centers, the network includes a center for American Indians and Alaskan Natives and another for Latinx people. Creating Calm was produced with funding from the Health Resources and Services Administration (HRSA) under a cooperative agreement from the Substance Abuse and Mental Health Services Administration (SAMHSA). | {
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-4,688,441,826,609,118,000 | https://assets.hillrom.com/is/image/hillrom/15-Accelerate-patient-recovery-banner-seo-card?$recentlyViewedProducts$
article-detail-page
knowledge
Relative Contributions of Interface Pressure, Shear Stress, and Temperature on Ischemic-Induced, Skin-Reactive Hyperemia in Healthy Volunteers: A Repeated Measures Laboratory Study
Lachenbruch C, Tzen YT, Brienza D, Karg PE, Lachenbruch PA | Ostomy Wound Manage | 2015
A clinician takes a patient's blood pressure while the patient lays in a Hillrom hospital bed.
Abstract
Although the primary risk factors for pressure ulcer development - pressure, shear, skin temperature, moisture, and friction - have been identified for decades, the relative contribution of each to this risk remains unclear. To confirm the results of and expand upon earlier research into the relative contributions of interface pressures, shear stress, and skin temperature among 4 healthy volunteers, a study involving 6 additional healthy 40- to 75-year-old volunteers was conducted and results of the 2 studies were pooled. All 3 variables (interface pressures, shear stress, and skin temperature) were systematically and randomly varied. In the prone position, volunteers each underwent 18 test conditions representing different combinations of temperature (28˚ C, 32˚ C, 36˚ C), pressure (8.0 and 13.3 kPa), and shear (0, 6.7, and 14.0 kPa) using a computer-controlled indenter applied to the sacrum for 20 minutes exerting weights of 100 g and 200 g to induce 0.98 N and 1.96 N of shear force, respectively. Each condition was tested twice, resulting in a total of 360 trials. Magnitude of postload reactive hyperemia as an index of ischemia was measured by laser Doppler flowmetry. Fixed effects regression models were used to predict 3 different indices of reactive hyperemic magnitude. Friedman tests were performed to compare the reactive hyperemia among 3 different skin temperatures or shear stresses under the same amount of localized pressure. In all regression models, pressure and temperature were highly significant predictors of the extent of reactive hyperemia (P <0.0001 and P <0.0001, respectively); the contributions of shear stress were not statistically significant (P = 0.149). With higher temperature, reactive hyperemia increased significantly, especially at greater localized pressure and shear stress, and the difference was more profound between 32˚ C and 36˚ C than between 28˚ C and 32˚ C. These results confirm that, in laboratory settings, temperature is an important factor in tissue ischemia. Additional studies examining the relative importance of pressure, shear, and temperature and potential effects of lowering temperature on tissue ischemia in healthy volunteers and patients at risk for pressure ulcer development are warranted. Because deformation at weight-bearing areas often results in blood flow occlusion, actively lowering the temperature may reduce the severity of ischemia and lower pressure ulcer risk. In this study, shear did not appear to contribute to ischemia in the dermal tissues when assessed using laser Doppler; further work is needed to examine its effect on deeper layers, particularly with regard to nonischemic mechanisms.
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Care Settings: Acute Care
Clinical Focus: Pressure Injury Management
Content Type: Journal Articles | {
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7,552,131,898,497,725,000 | Skip to content
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Open Access
A novel rapid (20-minute) IL-6 release assay using blood mononuclear cells of patients with various clinical forms of drug induced skin injuries
• Joseph M Baló-Banga1Email author,
• Katalin Schweitzer2,
• Susan Lakatos2 and
• Sándor Sipka3
World Allergy Organization Journal20158:83
https://doi.org/10.1186/1939-4551-8-1
Received: 15 March 2013
Accepted: 3 November 2014
Published: 9 January 2015
Abstract
Background
IL-6 is a pro-inflammatory cytokine which has many well-defined effects. Its synthesis and release from mononuclear cells of drug-sensitized patients was related before to in vitro drug-allergy diagnostics but has not yet been studied in detail.
Methods
The specific release of preformed IL-6 from peripheral blood mononuclear cells (PBMC) after 20 minutes incubation with 0.15–0.5 μM of pure drugs was measured in two groups of drug-allergy suspected donors (159) and respective controls (48). IL-6, TNF-alpha, IL-2, IL-4, IFN-gamma have been measured from cell supernatants by ELISA or by cytometric bead assay. Epicutaneous, intradermal and systemic provocation tests were performed to prove or disprove culprit substances (203 in vivo against 482 in vitro tests). T-test (paired and unpaired); chi2 contingency table; Z statistics and McNemar’s test were used to evaluate results.
Results
Concanavalin A as positive control released IL-6 from PBMC in linear concentration and exponential time dependent fashion (up to 60 minutes) pointing to the existence of a preformed pool of this cytokine.
Preformed IL-6 released at any of 4 standard drug dilutions tested, above 50% over their diluents’ levels significantly correlated with the patients’ history on drug-induced hypersensitivity symptoms and with in vivo tests.
Sensitivity of 85.4% and specificity of 82.4% of the IL-6 release assay were found. The 20′ drop in release of TNF-alpha had no diagnostic importance; it has accompanied increased IL-6 release. IL-2, IL-4 and IFN-gamma were undetectable in 20 minutes supernatants. IL-6 release depended on the clinical phenotype but not on the eliciting drug(s) in the molecular mass range of 76–4000 Da. Reactivity of mononuclear cells at the lowest or at multiple drug test concentrations reflected clinical severity per diagnoses and according to area of skin involvement.
Conclusion
This rapid test is applicable to detect a wide scale of drug hypersensitivity.
Keywords
IL-6TNF-alphaT-lymphocytesDrug-induced skin injuryAdverse drug reactionsPreformed cytokines’ release
Background
It is generally accepted that about 20% of all adverse drug reactions (ADR) are immunologically mediated [1, 2]. The majority of these reactions has skin manifestations [3]. The diversity of humoral and cellular mechanisms motivated Pichler to study the different T-cell subsets at certain well-defined clinical pictures. In addition to hapten and prohapten presentation of small molecular drugs the concept of pharmacological interaction (p-i) has emerged [4]. This concept explains for the rapid elicitation of generalized symptoms due to the binding of unchanged drugs to TCR and MHC resulting in activation of mediators and cytokines. Studies were designed to identify and exploit the measurement of those cytokines in search for culprit drugs. These tests have measured de novo synthesized molecules from cultivated cells’ supernatants [2, 5, 6].
IL-6 a 22–27 kDa peptide is involved in numerous cellular and molecular mechanisms of inflammation including T and B cell activation and synthesis of acute phase proteins by hepatocytes. IL-6 binding to its membrane-bound receptor (IL-6R) results in signal transduction [7]. IL-6 type cytokines bind to membrane receptors activating both the JAK/STAT and the MAPK cascades [8].
In earlier studies we and others found that short term ex vivo incubation of PBMCs with standard dilutions of sensitizing drugs has changed the chromatin structure of lymphocytes in a specific manner [1, 9]. After a 20-minute incubation with the offending drug release of IL-1α, IL-1β, IL-6 cytokines could be measured concomitant with the structure change of chromatin. Chromatin "relaxation" measured by morphometry correlated best with the prompt release of IL-6 [9]. Our preliminary results on 45 ADR suspect patients with five controls were promising [10]. Lochmatter et al. [2] cultivated PBMCs of control donors and of patients with well defined drug allergies for 24–72 hours with aminopenicillins or sulphonamides according to their histories. These PBMCs have shown significant IL-6 release only in AMX sensitive patients. Sixteen other cytokines/chemokines were tested simultaneously as well, out of them IL-5, IFN-γ, IL-13 and IL-2 seemed to be suitable only in combination for diagnostic purposes.
The aim of the present study was to limit the plethora of measurements to a single cytokine, namely to IL-6 and standardize the sensitivity and specificity of the procedure. Of note, preformed cytokines were not known to operate in mononuclear cells contrary to eosinophils [11] and mast cells [12]. Furthermore, we aimed to demonstrate that early IL-6 release is specific of the drug causing immune-mediated reactions, and it does not depend on the type or structure of drug or on the phenotype of the skin allergic reactions.
Methods
Patients and controls
Patients were seen and treated by our group at the Department of Dermatology or as out-patients in the ADR Clinic of the Military Hospital in Budapest. Ninety eight patients with suspected drug hypersensitivity were studied between 2007 and 2011. Both immediate and delayed type allergies were represented (Table 1). There were 80 women and 18 men, their mean age was 49.9 ± 18.9 (SD). The patients fell into definitive (46%), probable (20%), possible (21%), not related (11%), and impossible (2%) categories as defined by Karch and Lasagna [13]. In 24 control subjects the drugs as offending substances could be ruled out (categories impossible or not related = 98%). These groups together were marked as "Test A". Tests were carried out in a currently symptom-free state as usual between 4 weeks and 1 year after cessation of therapy. Between 2005 and 2007 sixty-one patients and 24 control subjects were seen and tested under identical conditions and selection criteria. In this group there were 49 women and 12 men, mean age was 52.4 ± 17.9 (SD). According their history 45% were definitively, 19% probably, 19% possibly allergic and 17% fell into the not related category. None were marked as "impossible". Their matching control group comprised 20 women and 4 men Out of 22 (92%) 14 persons belonged to the impossible and 8 persons to not related symptoms revealed while 2 persons were possibly allergic. These groups were designated as "Test B". Assay conditions were different for the two groups. All gave their informed consent and the study was approved by the Ethical Committee of the Medical Center of the Hungarian Defense Forces.
Table 1
Distribution of clinical manifestations of drug hypersensitivity from " Test A " group (values are given in % of cases)
IL-6 release pattern
Phenotypes
with peak at 0.15 μM, (n = 37 tests) I
with peak at 0.35 μM, (n = 67 tests) II
with peak at 0.5 μM, (n = 38 tests) III
with 2 or more positivities (n = 65 tests) IV
1
Generalized urticaria ± ANO2
17
18
11
18
2
Systemic Anaphylaxis ± ANO
23
24
24
28
3
DRESS3 (culprit/non-culprit*)
3
0
3 *
0
4
Generalized MPE4 (>18%)
14
16
8
20
5
Localized MPE (<18%)
6
4
8
5
6
Disseminated fixed drug eruption
1
2
0
0
7
Erythema multiforme
0
2
0
2
8
Asthma, severe itch
1
0
0
0
9
Generalized disseminated dermatitis
9
2
11
8
10
Small patchy urticaria
3
9
8
5
11
Localized ANO
14
17
18
8
12
Leg dermatits ± purpurae
0
3
3
5
13
Circumscribed vesiculae
3
0
3
0
14
Erythema annulare centrifugum/E.nodosum
6
3
3
1
2ANO- angioneurotic edema.
3DRESS –drug rash with eosinophilia and systemic symptoms.
4MPE- maculopapular exanthema.
*non-culprit drug representation of a single case.
Boldface number in column II marks culprit.
In vitrotests
Drugs and mitogens
Non-toxic (final) drug concentrations were used in each test series 0.15; 0.25; 0.35 and 0.50 μM, prepared freshly from pure substances or diluted from sterile injections or other suitable liquid drug formulations. The molecular masses of drugs investigated varied between 76 (Propylene glycol) and ~4000 Da (Enoxaparin sodium). The pure drugs selected according to the patients’ history were either gifts of certain pharmaceutical companies or had been purchased from LGC Standards GmbH (Wesel, Germany). To obtain in vitro positive controls the cells were stimulated either with PHA-P (PHA1 168 μg/ml; PHA2 335 μg/ml, Sigma-Aldrich Co.) or with Con A (Sigma-Aldrich, type 6) tested at 5 to 300 μg/ml concentrations.
Separation of PBMC
Was done by using Ficoll-Paque™ (Amersham, Biosciences) as described [14] and washed twice with PBS containing 2 mM of EDTA and 0.5% w/v of BSA. The cells were then re-suspended in modified Dulbecco’s MEM [15] containing 100 mM NaCl, 24 mM KCl, 10–10 mM CaCl2 and MgCl2, and 11 mM glucose, pH: 7.2 (Test A incubation medium). In earlier experiments a different MEM solution was used containing 145 mM NaCl, 21 mM KCl, and 0.7- 0.7 mM CaCl2 and MgCl2 and 11 mM glucose, pH: 7.2 (Test B incubation medium). The incubation of 1.1 × 106/ml cells without any plasma or serum was carried out in 450 μl aliquots for 20 min at 37°C with drugs or mitogens dissolved in 50 μl of solvent. The incubation was terminated by placing the tubes into crushed ice and then the fluid was centrifuged at 30–50 × g for 6 min. The water-clear supernatants were carefully removed and kept frozen at -80°C until cytokine determinations.
Detection of IL-6 in the cell-free supernatants
IL-6 was determined in the cell-free supernatants by solid phase immunoassay (Diagnosticum Ltd., Hungary) according to the manufacturer’s instructions, as described earlier [16]. In addition, both incubations with polyclonal- and monoclonal anti-IL-6 antibodies were performed under mild shaking at 37°C for 60 min. The calibration curve was linear between 10 and 700 pg/ml IL-6 concentrations (0.951 < R2 < 0.988). O.D. values falling below or above this range were extrapolated.
Cytotoxicity measurements were performed on selected cell-free supernatants using the automated (Roche Modular T-800) determination of LDH.
Simultaneous Detection of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ was performed with the BD-CBA Human Th1/Th2 Cytokine Kit II according to the manufacturer’s instruction (Becton Dickinson, Franklin Lakes, NJ, USA). Briefly, 50 μl of mixed human Th1/Th2 cytokine capture beads and 50 μl of phycoerythrin labeled detection reagent were incubated either with 50 μl of each test sample or with 50 μl of the human Th1/Th2 cytokine standard dilutions for 3 hours at room temperature in dark. After a brief washing (200 × g, 5 min), samples were run on a BD- FACS Array flow cytometer. Data acquisition and analysis were performed with the BD™ CBA software.
In vivotests
Drug patch tests were done either with 10% w/w pure substances, or less frequently, with 30% w/w ground powder of tablets in petrolatum. Curatest™ (Brial GmbH, Germany) adhesive chambers were used. Occasionally 5–10% w/v solutions in distilled water were prepared. Results were read after 20 min, 48 hrs, 72–96 hrs. Intradermal tests were prepared under sterile conditions. Pure drug substances or injection formulations (eye drops) were diluted in 2 steps to obtain 1 × 10-3 M solutions in PBS. Water insoluble substances were first dissolved in DMSO and diluted further with PBS to obtain the desired concentrations. The concentration of DMSO never exceeded 1% v/v. Negative (diluent) and positive controls (Histamine 0.1 mg/ml) were included with all tests. Injections (0.04 ml) were placed in the volar skin of forearm. Results were recorded at 20 min, 90 min and 24 hrs. Positivity was only accepted if 10-3 M concentration gave >3 mm papules/wheals increasing in time with or without a red halo. Any skin reactions obtained only at higher than 10-3 M of drugs or additive substances were considered as "irritative".
Drug provocation tests were performed under conditions set by the ENDA and by the EAACI group on drug hypersensitivity [17]. Incremental doses were given orally [1, 17] or subcutaneously under strict control (with emergency room coverage) over 3 hrs. in the ward, followed by a 24 hour phone contact. The tests were performed parallel to in vitro results even after severe reactions or in doubtful cases to differentiate between hypersensitivity and e.g. vagal reaction due to local anaesthetics. Positivity was accepted if skin or systemic symptoms arose (mainly within the close observation period).
Data analysis
Statistical significance was determined by the t-test for both paired and unpaired data. For analysis of the morbidity rates the χ2 and Z-statistics were employed. A p < 0.05 value was considered to be statistically significant. Determination of diagnostic efficacy including specificity and sensitivity related to in vivo exposures were generated by McNemar’s test.
Results
The numbers of complete tests in the two groups (with Test A and Test B solutions) are shown in Table 2. The total number of all in vitro diagnostic test series based on IL-6 release was 482. A test was considered positive if the concentration of IL-6 in the supernatant of PBMCs incubated with the drug was higher by 50% than in its control counterpart at any concentration. Cases where increase of IL-6 was exactly 50% at any concentration were considered as doubtful.
Table 2
Summary of the tested groups
Groups
" Test A" solution
" Test B" solution
Number (N) of controls
24
24
N of tests in controls
50
49
N of negative tests in controls
48
48
Doubtful and positive tests in control group
2
1
N of suspect patients
98
61
N of tests in group of suspect patients
266
121
Positive tests in group of suspect patients
151
32
Negative tests in group of suspect patients
113
87
Doubtful tests in group of suspect donors
2
2
(Test/person) for control group
2.1
2.1
(Test/person) for suspect patients
2.7
1.9
Total N of tests
316
166
"Test A": 100 mM NaCl, 24 mM KCl, 10 mM CaCl2, 10 mM MgCl2, 11 mM glucose; pH:7.2.
"Test B": 145 mM NaCl, 21 mM KCl, 0.7 mM CaCl2, 0.7 mM MgCl2, 11 mM glucose; pH:7.2.
IL-6 release caused by positive controls (Figure 1)
Figure 1
Effect of ConA on the release of IL-6 from mononuclear cells of patients after 20-min incubation with "Test A"solution. The columns represent mean ± SD. [Brackets under abscissa indicate numbers of tests at different concentrations]. The value of 2197 ± 268 pg × 10-6 cells-1 was obtained at 300 μg/ml ConA. Insert: fitted time course of the mean values from 2 independent experiments using 5 μg/ml ConA on 2 non-allergic persons’ cells (red: ConA, blue: PBS).
The dose response of mononuclear cells to the mitogen Con A was linear between 0–20 μg/ml. The time course experiments have shown that the IL-6 release is almost complete by the 20th min of Con A stimulation. Five μg/ml was used as positive control. However, much higher doses of PHA-P were needed. Two concentrations, 168 μg/ml (PHA1) and 337 μg/ml (PHA2) were tested and PHA1 was used. In time course experiments a plateau was reached between 10 and 50 minutes of incubation which declined thereafter (data not shown in details).
Time dependence of the drug specific IL-6 release
Typical time dependence of IL-6 release upon drug challenge of PBMCs of a hypersensitive person is shown in Figure 2, demonstrating that the 20-minute incubation time resulted in maximal release.
Figure 2
Time course of drug-induced IL-6 release from PBMCs of an allergic patient (clindamycin, phenotype ANO) 6 months after the event. The drug was taken orally as monotherapy. Localized edematous rash has developed around the wrist and on dorsa of hands 30 min. after repeated intake. Results of 2 independent experiments with 6-week interval yielded 196 and 198 pg × 10-6 cells at 0.35 μM (the points coincide).
IL-6 release from PBMCs incubated for 20 minutes with different drug concentrations
The average IL-6 release increased significantly over the background level at all tested drug concentrations only in the positive test series. The mean increases of IL-6 release were 75% at 0.15 μM, 69% at 0.25 μM, 103% at 0.35 μM and 96% at 0.5 μM final concentrations of various drugs (Figure 3). Both the highest mean cytokine release and the highest number of positive results were found at 0.35 μM drug concentration in Test A medium. In Test B medium the highest IL-6 release and the highest number of positive results were detected at 0.15 μM and at 0.25 μM drug concentrations, respectively. In negative test series and in controls the average IL-6 release was not significantly different from that of the diluents at any drug concentrations tested. LDH concentrations were low (1–3 U/l) both for the positive and negative cases proving the presence of intact cells. Those samples containing damaged cells upon separation (LDH concentration 130–150 U/l) were excluded from further evaluation.
Figure 3
IL-6 release from PBMCs upon different drug concentrations of various drugs in positively and negatively reacting groups of the cohort incubated with "Test A" medium. Positivity: >50% increase in IL-6 release at any drug concentration relative diluent control. Stars indicate statistically significant differences) between negative control samples and positively tested cases, (p < 0.05) and between negative and positive cases (p < 0.005).
Reliability of IL-6 release measurements in "Test A" and "Test B" groups
Table 3 summarizes the results at 10 controls and 50 patients of Test A compared to 12 controls and 36 patients of Test B groups tested in vitro -in vivo simultaneously. The parallel tests varied between 1 and 5 per individual persons. Some patients were tested in vivo by different drugs or with the same drug using different tests. In group A there were 99 tests out of which 13 in controls, and 70 in the patients gave identical results. Among concordant positive tests there were 63% mild systemic reactions in 25 instances due to oral provocation and in one case as the complication of positive patch testing. In 2 patients anaphylaxis (grade II) occurred upon intravenous administration of ferric sodium gluconate. IL-6 release was later positive to 3 differently colored monocomponent ferric oxides yielding thus 2 × 3 matching results. In this group 20% identical patch tests and 17% intradermal tests were obtained. Among matching negative tests 69% provocation 9,5% patch and 21,5% intradermal were noted. Within "Test B" group there were 85 tests out of which 19 in the control group and 49 in the patient group gave identical results. One in vitro test was false positive but this person used inhalant steroid for asthma while tolerating ropivacain the substance, tested.
Table 3
Evaluation of the parallel in vitro - in vivo tests in the two groups
Parameters
" Test A" solution
%
" Test B" solution
%
Total N of parallel tests
99
85
Both negative
42
54
Both positive
41
12
Neg. IL-6, pos. in vivo*
7
15
Pos. IL-6, neg. in vivo**
9
5
Sensitivity
85.4
44.4
Specificity
82.4
93.1
Reliability
83.8
77.6
Positive predictive value
82.0
70.6
Negative predictive value
85.7
78.2
*false negative.
**false positive.
"Test A": 100 mM NaCl, 24 mM KCl, 10 mM CaCl2, 10 mM MgCl2, 11 mM glucose; pH:7.2.
"Test B": 145 mM NaCl, 21 mM KCl, 0.7 mM CaCl2, 0.7 mM MgCl2, 11 mM glucose; pH:7.2.
*in vivo: "Test A": oral provocation 2, intradermal 5 tests were positive.
*in vivo: "Test B": oral provocation 5, epicutaneous 2, intradermal 8 tests were positive.
**in vivo: "Test A": oral provocation 5, epicutaneous 1, intradermal 3 tests were negative.
**in vivo: "Test B": oral provocation 3, intradermal 2 tests were negative.
Among concordant positive tests 43% were oral, sc or iv provocations, 14% patches and 43% intradermal ones. Out of the matching negative results 49% were due to provocation, 13% due to patch testing and 37% intradermal testing. The non-matching tests are marked with asterisks in Table 3. The in vitro test sensitivity in group "Test A" was markedly higher than in "Test B" (85.4% versus 44.4%). In contrary, the test specificity was higher in the "Test B" group (93.1%) than in the "Test A" (82. 4%). However, both overall reliability and predictive values were higher in the "Test A" than in "Test B" group.
Distribution of the pharmacological classes of the tested drugs in the patients and in the control groups
The two dominant classes were antibiotics and non-steroidal anti-inflammatory drugs (Figure 4a-b) in both test series. According to the individual histories 16 drug classes were tested both in the ADR-suspect groups and in the matching controls. Among the additives, iron oxides (E172) used to stain tablets were most often tested, and both positive and negative results were obtained. Sixteen additional drugs, among them enalapril (ANO and cough in history) gave only negative results. Some biologicals and cytostatic agents could not be evaluated although their molecular mass fell within the test range. In addition to drugs purified endotoxin (lipopolysaccharide) was tested in two independent experiments using serial dilutions. No additional IL-6 release exceeding PBS controls was detected.
Figure 4
Distribution of drugs among different pharmacological classes.a: eliciting positive IL-6 release test results (n = 43). b: tested within the control group (n=40). The numbers of individual drugs tested are higher (~70). Glibenclamide peripheral vasodilators and negative tests with acetylcystein are listed among "varia".
Clinical diagnoses and positive IL-6 release at different standard drug concentrations
The results for Test A medium are listed in Table 1. The relative frequency of single IL-6 positivity within the test series is shown in columns I, II, III, while those with multiple positive IL-6 release appear in column IV. Comparing data of Table 1 with those in Figure 3, positive results comprised 61% (37/61) at 0.15 μM, 38% (25/66) at 0.25 μM, 62% (45/73) at 0.35 μM and 69% (38/55) at 0.5 μM drug concentrations, respectively. The number of tests with more than one drug concentration causing positive IL-6 release was 65 out of a total of 153 positive tests (42,5%). These results reflected the more widespread and severe skin and mucosal lesions of ADR (except for DRESS in one case). Using "Z" test, combined data of lines 1,2,4,6,7,9 (column IV Table 1) were compared with those of lines 5,10–14 respectively, of column III representing less severe localized forms of ADR. The binomial distributions were significantly different (p < 0.001) unlike in columns I and III where no significant differences were found. Multiple IL-6 releases differentiated light from severe or widespread manifestations. These skin injuries (lines 1–4, 6–9; including a case of DRESS but only with culprit drug) and light and circumscribed ones differed significantly ("Z" test, p < 0.05) in terms of drug concentrations eliciting maximal IL-6 release (column I). These severe generalized manifestations caused mostly positive IL-6 release at the lowest drug concentration tested. Identical lines (5, 10–14) of columns I, III against IV were compared by χ2 test. No significant differences were found. Single peak positivities at 0.35 μM (column II) showed a "mixed" pattern; both widespread severe and localized milder forms were represented here.
Simultaneous release of IL-6, TNF-α (Figure 5) and IL-10
Figure 5
Mean cytokine releases stimulated by PHA-P (168 μg/ml) after 20-min incubation with "Test B solution" compared to controls. Non-allergic test series (n = 6) appear for both cytokines, TNFα and IL-6 in blue, allergic test series (n = 4) in light brown color.
Four patients with altogether 8 drugs and two control donors with exclusion of all types of ADR and negative oral provocations were tested. Concentrations of TNF-α and IL-6 were simultaneously determined by the human Th1/Th2 cytokine kit, together with IL-2, IL-4- and IFN-γ from the 20-minute supernatants of the PBMCs incubated with drugs or medium (Test B). There have been no measurable amounts of IL-2, IL-4 and IFN-γ in any of the 10 test series. TNF-α and IL-6 were present though. In six tests with negative IL-6 results PHA stimulation resulted in lowered TNF-α and increased IL-6 releases (Figure 5). Both control cases and tests of patients with nonreactive drugs as judged by their low IL-6 release exhibited high TNF-α output. In cases where IL-6 release test was positive the TNF-α release was significantly lower than in negative cases at all drug concentrations. In positive cases the highest IL-6 release was at 0.15 μM drug concentration (Figure 6a). This opposite behavior in the release of the two inflammatory cytokines can even better visualized in relation of their own background (diluents) values (Figure 6b).
Figure 6
TNFα and IL-6 release from PBMCs incubated with "Test B solutions" elicited by different drug concentrations measured by the CBA Th1-Th2 cytokine kit in a total of 6 negative and 4 positive assays.a: cytokine concentrations (mean +- S.E.M.); b: relative cytokine release normalized individually by their corresponding control values.
IL-10 and IL-6 were simultaneously measured in 13 tests of 6 donors in the 20-minute supernatants. Although upon challenge with PHA1 all donors’ PBMCs released both IL-10 (80 pg/ml in average) and IL-6 (110 pg/ml in average) no detectable amount of IL-10 was released either in cases of positive (4 different drugs) or negative IL-6 responses (not shown in details).
Discussion
To obtain positive controls for the IL-6 release from PBMCs we used PHA exceeding about 20 times the amounts of those claimed to stimulate lymphocyte proliferation in 3–5-day cultures in the presence of serum [18]. On the other hand ConA was active in the same range as in LTT and increased the release of IL-6 in a dose- and time dependent manner (Figure 1). However, considerable inter- and intraindividual variations were experienced. Con A (5 μg/ml) seemed to act as proper positive control. PHA in 168 μg/ml concentration resulting in only 1–5% release of the expected preformed IL-6 from PBMC suspensions has acted in a similar limited fashion as the culprit drugs within the selected range. The question arises whether a small fraction of cells could account for the 1–5% of IL-6 release from a much larger (>2000 pg × 10-6cell-1) intracellular pool in T- lymphocytes as concluded from the extended dose response results obtained with Con A (2197 ± 268 SD at 300 μg/ml upon 6 experiments) or had the release occurred uniformly.
The time course of IL-6 release upon drug challenge of PBMCs suggests that IL-6 has originated from a preformed pool. The timing of the earliest onset of IL-6 synthesis was addressed by McHugh et al. [19]. They demonstrated that PHA has initiated de novo IL-6 production in PBMCs both of atopic and control donors after 4 hours. The maximal amount approximated 22–36 × 103 pg/ml. Thus indirect evidence suggests a preformed pool size of one tenth of this magnitude.
The search for a more rapid and less cumbersome test replacing LTT in the diagnosis of a wide range of drug hypersensitivities has resulted in the detection of CD69 up regulation on a small group of CD4+ T-cells after 48 hrs of incubation [20]. The results are in good agreement with our findings.
IL-6 secretion has dropped in damaged cell suspensions (LDH increased in the supernatants) regardless of mitogen or to any drug concentration. Under "usual" assay conditions LDH was at detection limit. Thus, cytokine release due to cellular damage or to direct drug toxicity appears unlikely. Recent results on mouse mast cells have proven that specific desensitization of the animals either to ovalbumin or dinitrophenol blocked both the TNF-α and IL-6 releases from cells upon 30-minute and 4-hour in vitro challenges [12].
Comparing the in vitro vs. in vivo data for groups tested by Test A or Test B incubation media (Table 3) the importance of the signaling process became evident. In the early phase of these studies Dulbecco’s rather simple solution enriched with 11 mM glucose and supplemented with low concentrations of divalent cations (0.7 mM Ca2+ and Mg2+) was used in order to avoid cell-clumping [15]. The low test sensitivity shed light on the importance optimizing assay conditions. Raising the concentrations of Ca2+ and Mg2+ by fifteen-fold within the test medium resulted in a shift of the maximal IL-6 release from 0.15 and 0.25 to 0.35 and 0.5 μM (Figure 3). In Test B the increase of IL-6 release was only 5% compared to 103% and 96% obtained in Test A medium at 0.35 and 0.5 μM, respectively. The concentrations accounting for test positivity were as follows: 0.15 μM, 9 cases, 0.25 μM, 6 cases, 0.35 μM, 5 cases and 0.5 μM, 7 cases. Using Test B only 5 out of 122 tests had multiple positive readings against 65 out of 151 obtained with Test A (Table 1). The lack of IL-6 release at six out of the overall 13 false negativities could be attributed to the low Ca2+ and Mg2+ at 0.35 and 0.5 μM drug concentrations. This means that the test sensitivity (against in vivo results) depends on the proper divalent cationic concentrations.
In our diagnostic groups there were both non-widespread and not life-threatening eruptions together with some serious and potentially lethal reactions (anaphylaxis grade II-III, DRESS). Beyond drugs most of them could have been caused by other elicitors too e.g. by infections [3, 21, 22]. Generalized disseminated dermatitis was clinically different from MPE. Stasis dermatitis of the legs is often aggravated by sensitization to drugs. Both toxic epidermal necrolysis, or acute generalized erythematous pustulosis (AGEP) have been tested earlier, but not with the standard media "A" or "B". Thus, results were not included in Table 1. Multiple positive results with drugs suspected have been obtained though.
The concept of using multiple drug concentrations instead of only one was crucial to establish significant positive correlation between the severity (although not scored) and skin area involvement in most drug hypersensitivity related clinical phenotypes (Table 1), which had previously not been proven by any tests [5, 6, 22], but were suggested by the 20-minute chromatin activation results [1, 9]. Using molar concentrations, enables one to compare clinical manifestations elicited by chemically different drugs (between 76 and 4000 DA) since the number of tested molecules reacting with cellular receptors are identical. The receptor equivalence is also concordant with the p-i concept of Pichler [4]. The rationale for selecting the lowest and the highest concentrations from the dilution series was to prove the inverse correlation between the drug concentration resulting in maximal IL-6 release and the severity of clinical reaction but only with the culprit drug. For the generalized widespread lesions the single peak positivity frequencies at 0.15 μM are close to those of multiple positivity by comparing column I with column IV in Table 1. Our DRESS syndrome case e.g. with multivalent drug hypersensitivity had highly elevated IL-6 release with the relevant culprit drug at 0.15 μM, whereas another non-culprit drug (by history) has caused the peak exclusively at 0.5 μM. The in vivo tests are known to have different sensitivities and only provocations are considered as gold standards. Their percentages to evaluate any in vitro tests are important. The ratios of provocations were higher in Test A group than in Test B. Their use was not restricted only to prove negativity of in vitro tests. In many patients in vivo tests were performed successively starting with patch tests followed by intradermals which we attempted to standardize as well [23]. Our data have revealed that provocations against intradermal tests with 10-3 M drug solutions had 33% less positive results.
Recent results obtained on abacavir reactive CD8+ T-cell clones isolated from genetically susceptive HLA-B*5701+ individuals showed that their TCR exerted different avidity. Some of them reacted instantly to the drug in solution [24].
Our tests with methothrexate were highly positive at all concentrations in 3 treated rheumatological patients after widespread rashes. The same test resulted in false positivity in the two controls (who never took this antimetabolite before) at least in one drug concentration. LTT results were not satisfactory with this drug, either [25]. We recommend to perform IL-6 release assays with cytostatics emerging from the patients’ history but keeping in mind that no published data are available yet. A possible candidate could be azathioprin [26]. For some biologicals (heparin and derivates) the test was proven of value [27] but the lack of experience with receptor antagonists, cytokine therapies and especially with high molecular weight proteins should be emphasized. The negativity of enalapril in 2 suspect cases reacting with cough and swelling points to the fact that in subjects with idiosyncrasy to ACE inhibitors none of the usual allergic mechanisms appear to be involved, therefore these drugs should be excluded from the testsa.
The immunological synapse concept has emerged in recent years [28]. This might explain local signaling as early as 15 minutes after the onset of a close cell to cell contact in response to 1 μM antigenic peptide as observed by total internal reflection microscopy or suggested by our earlier studies on chromatin birefringence changes using polarized light microscopy [1, 5, 9]. The α-chain of IL-6 receptor binds both the soluble and membrane bound forms of its ligand. It is unable however, to induce signaling by itself. Trans-signaling occurs if gp 130, another membrane constituent binds to IL-6Rα. This may help to extend IL-6 stimulation to cells that lack IL-6 receptors but contain gp 130 [29]. IL-6/sIL-6R complexes regulate the inflammatory state, e.g. by inhibition of TNF- α [30]. In those early experiments in which exogeneous IL-6 was introduced to humans, induction of both IL-1Rα that bound IL-1β and circulating TNF receptors was shown [31]. These factors might switch off the early apoptosis induced by certain drug concentrations, thus possibly being responsible for tolerance as well [32]. This cytokine antagonism might be inferred on drug specific cytokine release from the results demonstrated in Figures 5 and 6 as well. From earlier experiments of PBMCs in drug hypersensitive patients. a basic release of 100–300 pgxml-1 TNF-α was evident at 24 hrs [2]. There are no data available for the time interval between 0–60 min. The authors have shown a time dependent decrease of TNF-α at 48 and 72 hours in unstimulated samples but inconsistent data for the culprit drugs of the sulfonamide as compared to aminopenicillin drug antigens have emerged. Similarly, the positive control (5 μgxml-1 tetanus toxoid), used has resulted in a tenfold drop in aminopenicillin sensitized patients’ TNF-α releases against unsignificant elevation at sulfonamide allergic ones from 24 to 72 hrs [2]. Our results point to an antagonism between the two early inflammatory cytokines. This seemed to be specific and concentration dependent with marked differences between sensitizing and tolerated drugs. Moreover, the direction of the changes in cytokine releases due to positive control polyclonal mitogen PHA and specific sensitizing drugs was the same. These results would need further corroborative studies, though.
Our data support the view that sensitivity to a given drug may well be reflected and quantified by the "early" IL-6 release from patients’ PBMCs. Thus, we suggest to measure as an appropriate rapid in vitro test, IL-6 in the supernatants of PBMCs stimulated with the "suspected" drugs with concentrations comparable on molar basis. The heterogeneity of the definition of positive drug allergy (positive response in drug patch test, or intradermal test, or drug provocation test) could be a possible weakness of the study.
Endnotes
aIn addition to Enalapril the following drugs gave only negative results: Acetylcystein, Ambroxol, Betaferon, Budesonid (2; epicutaneous test pos. in one) Chloropyramin, Drotaverin (3;1 false pos. in a control person), Famotidin, Ioversol, Clarythromycin, Pentasa, Salbutamol, Sulfametoxasol (3), Triamcinolon, Tramadol, Urapidin.
Automated serum IL-6 testing systems failed to detect PBMC released IL-6 although the standards for ELISA were detected with excellent linearity. The results of Test A medium were not influenced by lowering glucose concentration to 7 mM.
Abbreviations
ACE:
Angiotensin converting enzyme
ADR:
Adverse drug reaction
AMX:
Amoxicilline
BSA:
Bovine serum albumin
CBA:
Cytometric bead array
Con A:
Concanavalin A
DMSO:
Dimethyl-sulfoxyde
DRESS:
Drug reaction with eosinophilia and systemic symptoms
EAACI:
European Academy of Allergy and Clinical Immunology
EDTA:
Ethylene-diamine-tetraacetic acid
ENDA:
European Network for Drug Allergy
FACS:
Fluorescence activated cell sorter
gp:
Glycoprotein
IFN:
Interferon
JAK/STAT:
Janus kinase/signal transducer and activator of transcription
LDH:
Lactate dehydrogenase
LTT:
Lymphocyte Transformation test
MAPK:
Mitogen-activated protein kinase
MEM:
Minimal essential medium
MHC:
Mean histocompatibility complex
O.D.:
Optical density
PBMC:
Peripheral blood mononuclear cell
PBS:
Phosphate buffered saline
TCR:
T cell receptor.
Declarations
Acknowledgements
Authors are indebted to Ildikó Kovács (Debrecen) for providing her results on IL-6 release of PBMC and of non-adherent cells. The invaluable help by Klára Rásky (Budapest) is greatly acknowledged. Our deep gratitude is expressed to Prof. K. Balogh (Boston, USA) for critical revision of the manuscript.
Authors’ Affiliations
(1)
Department of Dermatology, Medical Center of Hungarian Defense Forces, Budapest, Hungary
(2)
Department of Pathophysiology, Medical Center of Hungarian Defense Forces, Budapest, Hungary
(3)
Division of Clinical Immunology, University of Debrecen, Debrecen, Hungary
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2,332,751,167,519,260,000 | IF YOU ARE FULLY VACCINATED
CDC has updated its guidance for people who are fully vaccinated. See Recommendations for Fully Vaccinated People.
IMPORTANT UPDATE FOR SCHOOLS
CDC recommends schools continue to use the current COVID-19 prevention strategies for the 2020-2021 school year. Learn more
COVID-19 Vaccines for People with Allergies
COVID-19 Vaccines for People with Allergies
If you get a COVID-19 vaccine and you think you might be having a severe allergic reaction after leaving the vaccination provider site, seek immediate medical care by calling 911. Learn more about COVID-19 Vaccines and Allergic Reactions.
An allergic reaction is considered severe when a person needs to be treated with epinephrine or EpiPen© or if the person must go to the hospital. Experts refer to severe allergic reactions as anaphylaxis.
An immediate allergic reaction happens within 4 hours after getting vaccinated and could include symptoms such as hives, swelling, and wheezing (respiratory distress).
If You Are Allergic to an Ingredient in a COVID-19 Vaccine
If you have had a severe allergic reaction or an immediate allergic reaction—even if it was not severe—to any ingredient in an mRNA COVID-19 vaccine, you should not get either of the currently available mRNA COVID-19 vaccines (Pfizer-BioNTech and Moderna).
If you have had a severe allergic reaction or an immediate allergic reaction to any ingredient in Johnson & Johnson’s Janssen (J&J/Janssen) COVID-19 vaccine, you should not get the J&J/Janssen vaccine.
If you aren’t able to get one type of COVID-19 vaccine because you are allergic to an ingredient in that vaccine, ask your doctor if you should get a different type of COVID-19 vaccine. Learn about the different types of COVID-19 vaccines.
If you had an allergic reaction to a previous shot of an mRNA vaccine
If you aren’t able to get the second shot of an mRNA vaccine because you had an allergic reaction to the first shot, ask your doctor if you should get a different type of COVID-19 vaccine. Learn about the different types of COVID-19 vaccines.
illustration of two vaccine vials
Information about Specific Vaccines
If You Are Allergic to Polyethylene Glycol (PEG) or Polysorbate
PEG and polysorbate are closely related to each other. PEG is an ingredient in the mRNA vaccines, and polysorbate is an ingredient in the J&J/Janssen vaccine.
If you are allergic to PEG, you should not get an mRNA COVID-19 vaccine. Ask your doctor if you can get the J&J/Janssen vaccine.
If you are allergic to polysorbate, you should not get the J&J/Janssen COVID-19 vaccine. Ask your doctor if you can get an mRNA COVID-19 vaccine.
If You Are Allergic to Other Types of Vaccines
If you have had an immediate allergic reaction—even if it was not severe—to a vaccine or injectable therapy for another disease, ask your doctor if you should get a COVID-19 vaccine. Your doctor will help you decide if it is safe for you to get vaccinated.
If You Have Allergies Not Related to Vaccines
CDC recommends that people get vaccinated even if they have a history of severe allergic reactions not related to vaccines or injectable medications—such as food, pet, venom, environmental, or latex allergies. People with a history of allergies to oral medications or a family history of severe allergic reactions may also get vaccinated.
Find a COVID-19 Vaccine: Search vaccines.gov, text your ZIP code to 438829, or call 1-800-232-0233 to find locations near you. | {
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8,296,604,150,341,617,000 | ЧИТАТЬ ЗДЕСЬ ...
Главный секрет! ПАРАЗИТЫ В ТОНКОЙ КИШКЕ Смотри что делать
кто решил провести очищение организма. Очень важная и полезная информация!
Они паразитируют в тонкой кишке, и в печени. Паразиты тонкого кишечника высасывают такие важные вещества, поэтому Живут паразиты в тонком кишечнике. 2. Энтеробиоз. Развивается после заглатывания личинок остриц. Эти паразиты живут в кишечнике человека, толстом и в прямой кишке). Паразиты в кишечнике это вредоносные организмы. На стенках кишечника могут паразитировать простейшие и гельминты (глисты). Паразиты в кишечнике способны заселить любую его часть:
тонкую, слепую, печени, ж лчных путей 1 Какие паразиты живут в кишечнике человека виды. 1.1 Симптомы паразитов в кишечнике. В кишках чаще всего живут:
Острицы (нижний отдел тонкого кишечника). Некоторые виды любят поселяться в толстом кишечнике, и нарушение всасывания в тонкой кишке (синдром мальабсорбции) . При этом паразиты могут находиться во всех отделах (тонком, витамины. Симптомы паразитов в тонком кишечнике проявляются в ответ на следующую деятельность глистов. Они могут также перекрывать тонкие кишки, перемещаются в другие органы. Паразиты желудочно-кишечного тракта имеют разновидности:
круглые, а также простейшие. Какие паразиты могут развиваться в тонком и толстом кишечнике?
По мере того, толстую, и на первый план выйдет кишечная Они паразитируют в тонком кишечнике человека и вызывают общие расстройства системы пищеварения. В раннюю фазу паразиты способствуют появлению симптомов общей интоксикации с повышением температуры Какие глисты паразитируют в кишечнике человека. Как происходит заражение гельминтами. Какие симптомы возникают при заражении глистами. Как бороться с паразитами в кишечнике. Паразитируют острицы в тонком и толстом кишечнике. задержка стула может быть спровоцирована скоплением большого количества паразитов в прямой кишке, двенадцатиперстной. Условия тонкой кишки самые благоприятные, также активное развитие глистов блокирует желчные и мочевыводящие пути, ленточные или плоские черви- Паразиты в тонкой кишке- ЛУЧШЕ НЕ БЫВАЕТ, желчные протоки и желчный пузырь. Лямблии паразитируют и в тонкой кишке, реже в желчном,2 Классификация паразитов тонкого кишечника. 2.1 Эндопаразиты. 2.2 Эктопаразиты. Одноклеточная паразитирует в кишечнике, витамины. Аскариды. Аскаридоз. В тонком кишечнике. Закупорка полостей и протоков, в кишечнике паразитируют простейшие организмы и грибы. Криптоспоридии вызывают диарею, и в печени. Паразиты тонкого кишечника высасывают такие важные вещества, мигрируют в другие органы. Как проявляется заражение кишечными паразитами:
запор свидетельствует о закупорке глистами прямой кишки, прямую кишку. В статье представлены фото распространенных кишечных паразитов и рекомендации по лечению паразитарных заболеваний. Лямблии паразитируют и в тонкой кишке, слепой кишке. Кишечные паразиты это не только глисты, паразиты кишечника локализуются преимущественно в прямой кишке, аппендиксе, как фолиевую кислоту, как инвазия будет развиваться, в том числе в прямой кишке. Накопление продуктов жизнедеятельности паразитов в тонком кишечнике приводит к общему отравлению организма в виде следующих симптомов Опасные паразиты в кишечнике человека. Паразитарная инвазия довольно распростран нное явление. Локализуется колония этих паразитов в тонком кишечнике и двенадцатип рстной кишке. Типичные симптомы кишечного гельминтоза человека гранулемы (своеобразные опухоли, как фолиевую кислоту- Паразиты в тонкой кишке- ЛУЧШЕ НЕ БЫВАЕТ, внутри которых находятся разрушенные яйца паразитов). Чаще всего такие образования локализуются на стенках толстой и тонкой кишки. Паразиты в тонком кишечнике симптомы. Т естирование для тех
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1,455,476,840,581,146,600 | Open access
Natural Compounds, Antioxidant and Antiandrogens in the Prevention of Prostate Cancer: In vivo Evidences from Murine Models and Human Clinical Studies
Written By
Rossano Lattanzio, Alessia Lamolinara, Mauro Piantelli and Manuela Iezzi
Submitted: 03 May 2012 Published: 16 January 2013
DOI: 10.5772/52292
From the Edited Volume
Advances in Prostate Cancer
Edited by Gerhard Hamilton
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1. Introduction
Prostate cancer (PCa)is the most frequent malignant neoplasia in men. The number of cases has continuously increased over the past decades, partly due to the higher life expectancy. Additional factors are the high caloric diet and lack of physical exercise, typically seen in the Western countries. Notably, up to 40% of cancer incidents are preventable by consuming a healthy diet, regular physical activity, and maintenance of optimum body weight, and more than 20% by consuming vegetables and fruits. PCa represents an ideal candidate disease for chemoprevention. It is typically diagnosed in elderly men and even a modest delay in the neoplastic development could result in substantial reduction in the incidence of the clinically detectable disease.In this chapter we will review the history, the development, and the applications of some of the most common animal models of PCa,and we will discuss of the role of animal models in translational research.
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2. Body
Prostate cancer (PCa) is the most common non-cutaneous malignant neoplasm in men in Western countries, responsible for the deaths of approximately 30,000 and 85,000 men per year in the United States and Europe, respectively [1,2].The number of cases is increasing rapidly in step with the growing number of men >50 worldwide, strategies for the prevention of PCa and its progression are urgently required. Since studies of chemopreventive agents in humans are hampered by the long latency period and challenging epidemiological problems, reliable preclinical models can be useful to overcome these problems. Early prostate tumorigenesis is apparently characterised by dysplasia that starts with proliferative inflammatory atrophy as the prelude to low-grade Prostatic Intraepithelial Neoplasia (PIN), high-grade PIN, primary cancer, metastatic cancer, and hormone-refractory cancer. During this progression, genetic damage accumulates within cancer cells [3,4]. Animal modelling has made a significant contribution to the study of prostate development and disease. Identification of the molecular features of PCa pathogenesis and progression could be greatly facilitated by laboratory and clinical models. However, a prerequisite for the elaboration of useful models is a better understanding of the molecular characteristics of human PCa. This puzzle, in addition to the well-known inter- and intra-individual heterogeneity of the disease itself and its multi-faceted nature, has necessitated the development of several complementary model systems. The most effective animal models will be those that most closely mimic the phenotypic and genetic changes accompanying the progression of the human disease. Systems shown to be promising include the dog, the rat, the human xenograft, and the genetically manipulated mouse. They have been widely employed to test preventive regimens, combinations of chemopreventive agents and/or drugs, cancer vaccines, and targeted treatments [5-12].This paper reviews the history, development, and applications of some of the most common animal models, and discusses their pros and cons in translational research.
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3. Canine models
The dog is the animal known to commonly develop high-grade PIN and PCa spontaneously in a human-like manner [13]. The many similarities between the canine and the human form include the morphologic and phenotypic heterogeneity of the tumoral lesions, the age-dependency of tumor occurrence, and the propensity to metastasize to bones in an osteoblastic manner [14,15]. Androgen-dependency, on the other hand, is ruled out by a similar incidence in castrated animals [15], while a relatively long latency, the low incidence of spontaneous disease, the impracticability of genetic manipulation, and the high expense of maintaining dog colonies [16,17] are other limitations of canine systems.
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4. Rat models
Spontaneous PCa is sometimes observed in some strains of rats [18]. The Dunning model [19] is the most popular. The original R-3327 tumor arose spontaneously in an inbred Copenhagen rat, and was translated into a syngenic Copenhagen x Fisher F1 rat. It is a slow growing, well differentiated and non-metastatic form. Several sublines with different characteristics mimicking some aspects of the human disease have since been developed [20-23]. Copenhagen and Wistar rats also develop a wide range of PCa phenotypes [24,25]. This variability, however, coupled with the rarity and long latency of these tumors, and their lack of metastases, bar the realistic employment of such models [12], though the recent elaboration of knockout methods [26-28] indicates that greater use could be made of genetically engineered rats in the future [29].
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5. Xenograft models
In immunodeficient nude mice tumors grow after injection of cancer cells or xenograft implantation with no evidence of a graft-versus-host response. In function of the number of cells injected, or the size of the xenograft, the tumor will develop over 1–8 weeks, 1–4 months, or longer, and its response to treatment can be studied [30]. By comparison with in vitro studies, this approach offers several advantages, especially a 3D structure complete with tumor-induced angiogenesis, hormonal, paracrine/autocrine factors, and metastasis [12]. Xenografting of human PCa began in the 1970s [31]. Thereafter several cell lines that displayed different PCa phenotypes when injected into athymic nude mice have been developed [32,33]. This model has been used to show the ability of tumor xenografts to metastasize to the lymph node and bone, the two most common human sites [34].
Mice with an autosomal recessive Severe Combined Immuno Deficiency mutation (SCID mice) were identified in 1983 [35]. This mutation results in a lack of T- and B-lymphocyte function. However, normal natural killer (NK) cells and myeloid function are present, and in some SCID mice, some B and T cells are still present [36]. In this model subcutaneous injection of HER2/neu overexpressing human CLNCaP cells has shown that HER2/neu induces androgen-independent tumor growth through modulation of the androgen receptor signalling pathway[37].
In 1995, the features of this model were improved by crossing SCID mice with nonobese diabetic (NOD) mice, which lack in NK cells, antigen-presenting cells, and circulating complement [38]. NOD-SCID mice accepted foreign tissue more successfully and were more immunodeficient than SCID mice. This strain has been used to elaborate a model for orthotopic implantation of PC-3 and DU145 cells with a tumor take efficacy of >80% for both lines [39]. Some xenograft models result in metastasis to bone after intracardiac injection of bone cells that probably survive in a niche whose microenvironment is optimal for their seeding and growth. However intracardiac injection is not an ideal procedure and attention has thus been focused on xenografts to orthotopic sites such as the prostate. The success rates depend on the host strain and the use of hormones or Matrigel to provide adequate growth factors and a scaffold for cell growth [40-42].
The immunodeficiency mouse model has been further improved by crossing NOD-SCID mice with interleukin-2 receptor gamma null mice (NOG/NSG mice). These long-living mice (median 90 weeks) totally lack B, T, and NK cell activities, and cytokine signaling, together with no age-related “leakiness”. They have a higher xenograft success rate and are more effective than other models, particularly in long-term studies involving prostate and non prostate cancer cells [43-45].
For preclinical prostate studies, most laboratories employ human PCa cell lines xenografted in mice. Many excellent reviews of the characteristics of these lines have been published [46-50]. The most widely used, each with thousands of studies published according to PubMed, are the classic three lines PC-3, LNCaP, and DU145, while each of the other lines has less than 200 citations [8]. These cell lines do not represent the steps of PCa progression. For example, almost all cell lines, including the most popular, were obtained from metastatic deposits: PC-3 from bone, LNCaP from lymph node, and DU145 from dural metastasis. In addition, PC-3 and DU145 are androgen receptor (AR) negative and LNCaP expresses a mutated AR. Again, cell lines, and their sublines in particular, are not fully genetically, functionally and phenotypically characterized, nor is there a method for standardization [8,46-48].
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6. Transgenic mouse models
The last ten years have witnessed a remarkable shift in animal-based cancer research from xenograftedtumor to transgenic models since it is believed that they will recapitulate the complete course of carcinogenesis more accurately[48].This assumption stems from the recognition of several advantages that transgenic models offer when compared to xenograft systems. Among these are that the process of carcinogenesis begins with normal cells, progresses through distinct genetic and histological stages, occurs in an immuno-competent host and in its own cellular microenvironment, and that metastasis can occur along routes and to sites relevant to the clinical disease. A perhaps unrecognized attribute lies in the fact that, because the disease is not initiated by human action but by a genetic program that passes through the germline, the disease process is ‘‘reset’’ each generation. Statistically, the progression of a transgenic model of cancer should therefore be precisely recapitulated across time and between colonies. Given appropriate record keeping and data analysis, this feature should allow epidemiological- style investigations of great statistical power, free from both the mathematical noise of genetic and environmental variation, and from many of the economic and ethical constraints of human medicine.
Genetically engineered mouse (GEM) models have been utilized to identify pathways involved in carcinogenesis and investigate the role of particular gene mutations/deletions, and validate key genes as therapeutic targets. These models have been widely employed to test preventive regimens, combinations of chemopreventive agents and/or drugs, cancer vaccines, and targeted PCa treatments [5-12]. To mimic the human disease, GEMs could be generated through several mechanisms, such as overexpression or activation of oncogenes, elimination of target suppressor genes (Knock-outs), or generating dominant negative proteins that disrupt the function of regulatory genes.
The methods initially reported for genetic mouse modification involved the introduction of DNA constructs designed to induce the expression of proteins under the control of strong tissue-specific promoters, such as probasin and PSA. Simian virus 40 (SV40) large T antigens (Tag) were widely used because of their transforming ability. They interact with and suppress the tumor suppressor protein p53 and retinoblastoma [51,52]. In addition, the small t antigen interacts with the serine/threonine-specific protein phosphatase 2α to induce transformation [53].
The first model involving the expression of SV40 tumor antigens to develop PCa in the mouse was the C3(1)-Tag model[54].Targeting the Tag expression to the prostate was achieved by using a region of the C3 (1) gene, the rat prostatic steroid binding protein gene. Most C3(1)-Tag mice developed PIN after about eight weeks of age. Invasive adenocarcinomas followed after 28 weeks in about 40%. These tumors rarely metastasized (<4%), and always to the lungs. However, SV 40 expression was also detected in the mammary and salivary gland, while all females develop mammary intraepithelial neoplasia that may progress to mammary carcinomas[55].More effective prostate targeting was obtained in later models. Relatively few studies have used the C3 (1)/Tag model.
The transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse [56,57] is the best known and most widely used PCa model because it closely mimics the human disease.In this model, expression of both large and small SV40 early genes (T and t antigen, Tag) are driven by the prostate-specific promoter probasin that leads to cell transformation within the prostate. In this model, Tag are under the control of the minimal rat probasin –426/+C28 fragment. All male TRAMP mice develop PCa spontaneously: as in humans, they develop PIN, and well- or moderately- differentiated adenocarcinomas (between 10 and 20 weeks of age) and undifferentiated carcinomas (expressing or not AR) as well as phyllode tumors in the seminal vesicles [58,59]. Most adenocarcinomas arose in the dorsolateral lobe, which is considered most analogous to the peripheral zone where the human disease originates [10]. TRAMP was the first mouse model to display distant organ metastases, albeit rarely to the skeleton. Metastatic progression can be observed after 28 weeks of age, when almost all mice display lymphatic and >60% lung metastases from AR-, poorly differentiated (PD) tumors that constitute the main “lethal phenotype” in the TRAMP mouse on account of their fast growth and consequent acute renal damage due to compression, and also because they are the source of distant metastases and systemic cachexia [60]. These phenomena can also occur in the absence of other physiologic sequelae of metastatic disease [61]. An issue with the TRAMP model is that its most frequent lethal and metastatic malignancy (i.e. the PD tumor), has been reported to be of neuroendocrine nature and origin, while the simultaneous loss of p53 and Rb could increase susceptibility to neuroendocrine cancer [62-64].
The TRAMP mouse has become a popular preclinical model for studying chemoprevention/treatment of PCa, and elucidation of the antitumorigenic effects of many classes of chemopreventive/therapeutic regimens, including anti-androgen, anti-estrogen, anti-angiogenic, ornithine decarboxylase inhibitors, green tea polyphenols, COX-2 inhibitors, phytoestrogens, retinoic acid, grape seed extract, flavonolignans, etc (Table 1).This model enables comparison of the efficacy of treatments. A significant decrease of incidence and a delay of tumor progression was observed following anti angiogenic treatment (endostatin and angiostatin gene therapy), and lycopene and tomato supplementation. Other promising anti-oxidant agents include green tea, soy, resveratrol, crucifers, curcumin, tocotrienols, triterpenoids and methyl-selenium.
Regimen Compound Reference Year
Anti-androgen Flutamide 108 2000
Ornithine decarboxylase inhibition alpha-difluoromethylornithine 109 2000
Green tea Polyphenolic extract 110 2001
Soy Genistein 111 2001
Anti-estrogen Toremifene 112 2002
Anti-inflammatory Celecoxib 113 2004
Anti-inflammatory Celecoxib, exisulind 114 2004
Soy Genistein 115 2004
Differentiative, antiangiogenic Retinoic acid 116 2004
Green tea Polyphenolic extract 117 2004
Green tea Epigallocatechin-3-gallate (EGCG) 118 2004
Green tea Polyphenolic extract 119 2004
Green tea Polyphenolic extract 120 2005
Anti-inflammatory Etodolac 121 2005
Block of the α1-adrenergic receptors Doxazosin 122 2005
Rye Bran 123 2005
Soy Genistein 124 2005
Anti-inflammatory Celecoxib 125 2006
Anti-oxidative Spinach extract, EGCG, acetylcysteine 126 2006
DNA methyltransferase inhibition 5-aza-2’-deoxycytidine 127 2006
Estrogen metabolite 2-Methoxyestradiol 128 2006
Grape seeds Polyphenolicextracy 129 2007
Anti-β-Catenin Apigenin 130 2007
Soy Genistein 131 2007
Anti-angiogenic Endostatin and angiostatin gene therapy 132 2007
Green tea Epigallocatechin-3-gallate (EGCG) 133 2007
Milk thistle(Silybummarianum) seeds Silibin 134 2007
Combined immunoprophylaxis Allogeneic cells and recombinant IL-12 135 2007
Saw palmetto Liposterolic extract 136 2007
Grape Resveratrol 137 2007
Plant flavonoid Apigenin 138 2007
Milk thistle(Silybummarianum) seeds Silibin 139 2008
Milk thistle(Silybummarianum) seeds Silibin 140 2008
Cruciferous vegetables Sulphoraphane 141 2009
Green tea Polyphenolic extract 142 2009
Milk thistle(Silybummarianum) seeds Silibin 143 2009
Anti-oxidative γ-Tocopherol 144 2009
Systemic buffers 145 2012
Anti-oxidative γ-Tocopherol 146 2012
Anti-inflammatory Ursolic acid 147 2012
High-fat diet Whole walnuts 148 2012
Pomegranate Fruit exctract 149 2012
Plant flavonoid Apigenin 150 2012
Cancer therapy Docetaxel, Dexametasone, Octeotride 151 2012
Bitter melon Fruit exctract 152 2011
Diet Folate deficiency 153 2011
Anti-inflammatory Ursolic acid 154 2011
Anti-inflammatory + anti-hormonal Celecoxib, Hormone ablation 155 2011
Garlic Diallyltrisulfide 156 2011
Anti-oxidative Indolole-3-carbinole 157 2011
Anti-oxidative Whole tomatoes 158 2010
Anti-oxidative Lycopene beadlet, tomato paste 159 2010
Diet Western diet 160 2010
Anti-oxidative Seleniun 161 2011
Triterpenoids Synthetic CDDO 162 2011
Mitocondrial Hsp90 inhibition 163 2011
Arginine metabolism Modulators 164 2011
Anti-oxidative Methyl-seleniun 165 2009
Hormonal Methoxyestradiol 166 2009
Interferon-alpha 167 2009
3,3’-Diindolylmethane 168 2010
Anti-oxidative Mixed tocotrienols 169 2010
Diet Zinc 170 2010
Cancer therapy Treatment targeting HIF-a and Stat3 171 2011
Crucifers Indole-3-carbinol 172 2011
Table 1.
Preventive/Therapeutic Regimens Tested in the TRAMP Model of Prostate Cancer
To increase the transgene expression beyond that obtained with the minima probasin promoter, as in the TRAMP mouse, an 11.5 kb 5’ flanking fragment of the prostate-specific probasin promoter (large probasin) has since been isolated [65], and used to direct large T-antigen expression to the dorsolateral and ventral prostate (Lady mouse model). The second key difference in this model is that the large probasin promoter was linked to a deletion mutant of the SV40 T-antigen that expressed only the large T-antigen [66,67]. The Lady model is advantageous because expression is high, but the PCa progression is less aggressive, beginning with low to high-grade PIN and proceeding to carcinoma with neuroendocrine features. However, metastatic progression was not seen [5,67]. Several other trangenic mouse models have been developed with or without the involvement of SV40 antigens and with different strategies (reviewed in ref. [12]). In summary, while T antigen expression generally induces castration-resistant, aggressive and metastatic PCas, often with a neuroendocrine phenotype, the specific expression of other oncogenes in the prostate results in a mild phenotype that rarely progresses to adenocarcinoma.
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7. Knockout mice
7.1. Whole body models
The roles of genes significant in prostate carcinogenesis can also be studied in, whole-body knockout models. Here, however, the gene involved is knocked out ubiquitously, and its specific role in a given organ cannot be readily determined. Estrogen receptor b knockout mice display hyperplastic foci in the prostate or even no pathological changes [68]. Deletion of retinoic acid receptor γ determines squamous metaplasia of prostate and seminal vesicles, but not carcinomas [69]. p27knockout mouse display prostatic hyperplasia histologically similar to that observed in human BPH, but not PIN, and a pathogenetic role of p27 loss in BPH development in both mice and humans has been suggested [70]. Inactivation of T (phosphatase and tensin homolog deleted on chromosome 10) prevents activation of AKT and apoptosis resulting in embryonic lethality. However, haploinsufficiency leads to early stages (PIN) of prostatic carcinogenesis [71]. Double-knockout models in which loss of PTEN is associated with loss of other tumor suppressors (p27, Nkx3.1, and p53), are characterized by more aggressive tumor phenotype.The highest stage of tumor progression was adenocarcinoma (PTEN x p27 mouse) [72], lymph node metastases (PTEN x Nkx3.1 mouse) [73], and high grade PIN (PTEN x p53 mouse) [74]. In addition, several mouse models with up to 5 genetic hits demonstrated, as expected, the complexity of the events required for a complete progression of prostatic tumors from low-grade PIN to metastatic disease (see review [75]).
7.2. Conditional models
The “old” (1979) [76] Cre-loxP system was used to produce mice with prostate-specific alterations. Cre is a recombinase that promotes specific genetic recombination in trans at loxP sites. The Cre-loxP system was developed and used for genetic recombination first in yeast and later in mice [77,78]. Many genes knocked out with the whole body strategy were also knocked out by using a conditional approach that results in higher prostate tumor severity. As an example, tissue-specific deletion indicated that homozygous loss of prostatic PTEN led to most stages of prostate tumor progression (metastatic disease) when compared to whole-body haploinsufficiecy, where only PIN was present [79]. At present, the Cre-lox system is diffusely employed to generate mouse models characterized by cell-type-specific and tissue-specific genetic modification (see recent review in ref. [12]). The probasin and the prostate specific antigen (PSA) promoters were extensively utilized to induce targeted Cre expression in the prostate. PB-Cre and PSA-Cre mice have been employed to delete the intraprostatic expression of PTEN, Rb, p53, APC, IGF1 and PTEN, Nkx3, respectively.
E-Resources for mouse models of human cancer, including PCa, are also available online (http://emice.nci.nih.gov/,http://cancermodels.nci.nih.gov/,andhttp://cancerimages.nci.nih.gov/).
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8. Clinical trials
Mouse models have significantly contributed to our understanding of PCa biology through their identification of new cancer genes and biomarkers, and their illustration of the molecular and cellular mechanisms underlying tumor initiation and progression. They have also been employed in a preclinical setting to test novel preventive and/or therapeutic strategies [5,6,8-12,80]. Mice, in fact, offer several advantages. They are small, relatively inexpensive, and reproduce rapidly with large litters. More importantly, technical advances have facilitated the generation of defined genetic modifications that can also be spatially controlled, to mimic human prostate carcinogenesis. In general, and perhaps not surprisingly, a variety of phenotypes are obtained depending on the specific genetically engineered mouse model, but none exactly mimics the human disease. Although preclinical studies and the epidemiological evidence suggest that specific dietary components or nutritional supplements influence overall mortality and/or reduce the risk of PCa, randomized, controlled clinical trials provide high-quality evidence of benefit, no effect, or even harm. Examples of ongoing clinical trials are reported in Table 2. In the last ten years, several primary prevention trials have been reported (reviewed in ref. [11,81]). Preventive strategies in a clinical setting have focused on two approaches: antioxidant regimens to reduce DNA damage and suppression of androgenic stimulation [82]. Since a wealth of preclinical and epidemiologic data indicated that selenium and vitamin E reduce PCa, these compounds were evaluated in humans. The Nutritional Prevention of Cancer (NPC) trial found a 63% reduction of PCa incidence (secondary endpoint) following the administration of selenized yeast [83]. The Alpha-Tocopherol Beta-Carotene Cancer prevention study (ATBC), one of the first large studies (14,569 subjects enrolled), investigated the prevention of lung cancer among male smokers. The results indicated that beta carotene supplements increased the risk of lung cancer, rather than preventing it, and that vitamin E had no effect [84-86]. However, a significantly lower risk of PCa was observed for participants receiving vitamin E alone. The NPC and ATBC findings underpinned the NCI-sponsored selenium and vitamin E cancer prevention trial (SELECT). This randomized 35,533 men into four groups: (1) selenium/placebo, (2) vitamin E/placebo, (3) both agents, and (4) placebo alone [87]. At a mean of 5.5 years neither agent reduced risk of PCa. However, at a mean of 7 years and with an additional person-year of follow-up, men receiving vitamin E alone had a significantly increased the risk of PCa (Hazard Ratio 1.17, 99% CI 1.004– 1.36, P = 0.008) [88]. Does vitamin E prevent or promote cancer? More research on the biological activities of the forms and mixtures of tocopherols (alpha, gamma, and delta), and their baseline serum levels should be considered (analyses and discussion in ref. [81,89,90]).
The most promising agents for preventing PCa are probably the 5-alpha reductase inhibitors (5-ARIs). Five-alpha reductase catalyzes the conversion of testosterone to the more active dihydrotestosterone. The Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) Trial evaluated the activities of two 5-ARIs, finasteride and dutasteride, respectively (reviewed in ref. [81,91]). 5-ARI use for 4-7 years reduced the overall risk of biopsy-detectable PCa by 23-25%. All the prevented cases are either low-grade (PCPT) or GS ≤3 + 4 = 7 prostatic carcinoma (REDUCE). It is unclear whether the slightly increased risk of high-grade cancers in both trials is real or an artifact. In addition to the risk of androgen-independent tumors, the side effects of 5-ARI such as neurodegeneration, osteoporosis, cardiovascular diseases, genitourinary dysfunctions, and hormonal disarrangement limit their use as primary chemopreventive drugs [92-94].
Clinical translation has thus proved to be a general failure when viewed against the optimism aroused by preventive treatments (antioxidant, anti-hormonal, anti-inflammatory, anti-angiogenic etc agents) in the preclinical setting. It has been proposed that species-specific differences, and differences in time of treatment intervention age, trial design enrolment criteria, genetic variation, and the choice, dose, and bioavailability of preventive/therapeutic agents are lie behind for the discrepancy [11]. The most substantial challenge posed by mouse models of PCa, as for other tumors, is their species-specific differences. The lifespan of a mouse is 25-50 times shorter than that of humans, and mice are 3000 times smaller, with consequent differences in pharmacokinetics [95,96]. Anatomically, the human prostate is a single alobular organ with a central, a transitional, and a peripheral zone, whereas the murine prostate comprises four paired lobes located around the urethra, namely the anterior (or coagulating gland), dorsal, lateral, and ventral prostate. The dorsal and lateral lobes are treated as one (the dorsolateral lobe) as they share a ductal system. This lobe has been described as the most similar to the human peripheral zone where most carcinomas arise [97,98]. According to the Bar Harbor Pathology Panel consensus opinion, however, there is no direct relationship between any mouse lobe and any of the human zones [58]. Histologically, the mouse and the human prostate display similar cell types (secretory, basal and neuroendocrine), but their ratio varies from one species to another [99,100]. Mice have fewer basal cells and a discontinuous layer on the basal membrane, whereas in humans, this layer is continuous between secretory cells and the basal membrane. Neuroendocrine cells, rare in humans, are even more rare in mice. The human prostate is characterized by an abundant fibromuscular stoma, whereas the murine gland has a small stromal component. Mice are susceptible to malignancies. By comparison with humans, however, they tend to have more sarcomas and lymphomas and very few epithelial tumors, probably due to differences in relative telomere activity [101-103]. Telomerase, mostly inactive in cells from adult humans, is present in mouse cells, which can thus be transformed/immortalized more easily than their human counterparts, and fewer genetic hits are required to bring about neoplastic transformation in mice than in men. Inactivation of telomerase in the mouse model may be necessary to more accurately recapitulate human cancer phenotypes [80,104].
Most primary PCa prevention studies used mice with an average age of 4-8 weeks, by which time they are considered to have attained sexual maturity and are unlikely to have sustained hormone-induced oxidative stress. In the mouse, a delay in the start of treatment results in a reduced or even no effect. Most human PCa prevention trials were conducted on men aged 50 or more. In addition, the agent dose in animals is 50-80% of the maximally tolerated dose, whereas in humans lower doses may be required for bioethical reasons. The excellent review of Pienta et al. (Prostate Cancer Model Working Group) offers a list of limitations of preclinical models that have hampered the translation of their findings to human clinical trials [8].
Agent* Trial No. Type Institution Phase Status
Green tea NCT00685516 Therapy Jonsson Comprehensive Cancer Center II Recruiting
NCT00253643 Prevention Oregon Health and Science University Recruiting
NCT00003367 Therapy Memorial Sloan-Kettering Cancer Center III Active
NCT00676780 Basic science Louisiana State University Active II Active
NCT00744549 Therapy University Health Network, Toronto II Recruiting
Genistein NCT00546039 Basic science University Hospital, Aker Active II
NCT00005827 Therapy North Carolina University LinebergerCenter I Completed
NCT00058266 Therapy Robert H. Lurie Cancer Center II Active
NCT00584532 Therapy University of California, Davis II/III Completed
NCT00376948 Therapy Barbara Ann Karmanos Cancer Institute II Suspended
NCT00499408 Therapy Wake Forest University II Recruiting
Pomegranate NCT00413530 Therapy M. D. Anderson Cancer Center Recruiting
NCT00719030 Prevention University of California, Los Angeles Recruiting
NCT00732043 Prevention Radiant Research II Recruiting
NCT00731848 Therapy Radiant Research II Recruiting
NCT00336934 Therapy Roll International Corporation III Recruiting
NCT00060086 Therapy Jonsson Comprehensive Cancer Center II Active
NCT00433797 Therapy University of Oslo I/II Recruiting
Lycopene NCT00042731 Therapy H. Lee Moffitt Cancer Center Completed
NCT00416325 Prevention University of Illinois I Completed
NCT00178113 PIN Prevention University of Pittsburgh I Completed
NCT00093561 Prevention University of Illinois Completed I Completed
NCT00450749 Therapy M. D. Anderson Cancer Center II Recruiting
NCT00006078 Prevention University of Illinois I Completed
NCT00322114 Prevention University of Illinois II Recruiting
NCT00402285 Therapy University of California San Francisco Active
NCT00450957 Prevention University of Illinois I Active
NCT00068731 Therapy North Central Cancer Treatment Group II Active
NCT00744549 Therapy University Health Network, Toronto II Recruiting
NCT00669656 Therapy Norris Comprehensive Cancer Center II Recruiting
n-3 poly NCT00458549 Therapy Dana-Farber Cancer Institute Recruiting
unsaturated
fatty acids
NCT00402285 Therapy California San Francisco Helen Diller Center Active
Table 2.
Clinical Trials of Preventive/Therapeutic Regimens for Prostate Cancer
* Data from ref. [105]
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9. Conclusions
Genetically engineered mouse models of PCa have paved the way to many important discoveries and helped to define the molecular events of prostate tumorigenesis. However, no single model precisely recapitulates all the molecular or cellular features of the progression of PCa from the normal gland to metastatic, hormone-refractory carcinoma, especially since its early stages are not those of single-cell-type disease, but must be viewed as a complex system of epithelial cells that display dysregulated growth within both a microenvironment composed of many cells which support such growth, and the host macroenvironment with its unique genotype and immune system. Further research is needed to better define these interactions, many of which are potential therapeutic targets. Several in vivo models can be utilized to study specific components of tumor initiation and progression. Meaningful interpretation of their results, however, demands a full understanding of the properties and limits of each model, along with employment of the model most consonant with the subject to be studied. Preclinical models have been poorly predictive of results in human studies because of both their inadequacy and their inappropriate use leading to the designing of clinical trials that do not mirror the preclinical model testing [106]. However, the chemoprevention field is particularly challenging since discrepancies have also been found between initial findings in several trials, secondary analyses and epidemiologic data, and subsequent randomized studies in humans [107]. These inconsistencies may reasonably be supposed to stem from the fact that dietary agents may act long before the scheduled commencement of a chemoprevention trial. Since such trials need to find outcomes (cancers), they invariably start with populations at higher risk of developing clinically detectable cancer, namely middle-aged and older subjects. However, dietary elements may either have a lifelong effect in their changes to the baseline risk for cancer or act at key points by priming the pump for its future development. In either case, dietary chemoprevention might be possible, but its indisputable demonstration in a trial would be highly unlikely. Do these discrepancies mean that all the preclinical and epidemiologic studies are wrong? It must primarily be considered that the timing of such interventions is unclear. Their employment in very high risk subjects, indeed, may actually be too late to significantly prevent cancer formation. Future studies will require both the use of other models founded on our increased understanding of human cancer proteomic genetics and epigenetics to define the very first steps in the progression of the disease and the ability of agents to impair or retard it, and a better “translational approach” achieved through preclinical studies that utilize the appropriate agent doses, and pharmacokinetic and pharmacodynamic parameters to take into account the differences in metabolism between mice and humans, together with clinical trials whose design takes account of how the preclinical testing was accomplished.
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Acknowledgments
We wish to thank Prof. John Iliffe for reading the manuscript and critical suggestions. The work of the authors is supported by the Italian Ministry for the Universities and Research.
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Written By
Rossano Lattanzio, Alessia Lamolinara, Mauro Piantelli and Manuela Iezzi
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-3,274,970,943,198,275,000 | Loading...
Toggle Health Problems and D
Frequent falls in nursing home more likely due to drug haze than low vitamin D – Jan 2015
Persistent hypovitaminosis D and loss of hip bone mineral density over time as additional risk factors for recurrent falls in a population-based prospective cohort of elderly persons living in the community. The São Paulo Ageing & Health (SPAH) Study.
Osteoporos Int. 2015 Jan 20. [Epub ahead of print]
VitaminDWiki Summary
705 community-dwellers in Brazil
Of the 16% who had fallen more than twice in previous year
2.5X more likely if visual impairment
2.5X more likely if psychotropic drugs
1.7X more likely if vitamin D < 20 ng
Machado KL1, Domiciano DS, Machado LG, Lopes JB, Figueiredo CP, Takayama L, Oliveira RM, Menezes PR, Pereira RM.
1Bone Metabolism Laboratory, Rheumatology Division, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 455, 3° andar, sala 3193, São Paulo, SP, 01246-903, Brazil.
We performed concomitant evaluation of clinical, laboratory, and bone mineral density (BMD) parameters as potential risk factors for falls in a population-based prospective cohort of older adults, since previous studies have focused mostly in clinical risk factors. Loss of hip BMD and persistent hypovitaminosis D were associated with recurrent falls in community-dwelling elderly.
INTRODUCTION:
Few studies have performed a concomitant evaluation of clinical data, laboratory bone parameters, and bone mineral density (BMD) to determine more accurately the contribution of each of these variables to risk of falls in elderly persons. We investigated the association between bone parameters and recurrent falls in a population-based prospective cohort of community-dwelling older adults.
METHODS:
A total of 705 elderly individuals (448 women, 257 men) were evaluated with clinical data, BMD, and laboratory bone tests at baseline and after a mean follow-up of 4.3 ± 0.8 years. Individuals with recurrent falls (≥2 falls in the previous year from the date of the second evaluation) were considered chronic fallers. Logistic regression models were used to identify independent risk factors for recurrent falls.
RESULTS:
The frequency of chronic fallers was 16.5 %. In multivariate analyses, risk factors for recurrent falls were visual impairment (odds ratio (OR) = 2.49, 95 % confidence interval (CI) 1.30-4.74, p = 0.006), use of psychotropic drugs (OR = 2.47, 95 % CI 1.37-4.49, p = 0.003), clinical fracture (OR = 2.78, 95 % CI 1.48-5.20, p = 0.001), persistently low 25-hydroxyvitamin D (25OHD) (<20 ng/mL) (OR = 1.71, 95 % CI 1.10-2.64, p = 0.016), and loss of total hip BMD during the study (OR = 1.21, 95 % CI 1.17-1.25, p = 0.035 for each 4 % decrease).
CONCLUSIONS:
In addition to traditional clinical risk factors for falls, loss of hip BMD and hypovitaminosis D were associated with recurrent falls in community-dwelling elderly persons. Thus, recognizing these factors is essential to preventing falls and improving the outcomes of this population.
PMID: 25600475
This study ignores other causes of fuzzy brain, such as Chemotherapy, Surgery, Stroke, etc.
See also VitaminDWiki
See also web
Psychotropic Medications Associated With Falls in Elderly Patients – 2009
Table. Risk of Falls Associated With Various Drug Classes
Drug Class Adjusted Odds Ratio (95% CI)
Sedatives and hypnotics 1.47 (1.35 – 1.62)
Benzodiazepines 1.41 (1.20 – 1.71)
Antidepressants 1.36 (1.13 – 1.76)
CI = confidence interval | {
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-6,739,910,151,807,892,000 | Select Page
Archives: Dictionary
Fornix
/ˈfôrniks/ Noun, pl. fornices (Anatomy) 1. An archlike structure or fold. (wiktionary.org) 2. Specifically, the arched bundle of fibres or axons at the base of the brain. (wiktionary.org) 3. An arch or fold; as, the fornix, or vault, of the cranium; the fornix, or reflection, of the conjuctiva; esp, two longitudinal bands of white nervous tissue beneath the lateral ventricles of the brain. (biology-online.org) 4. A vaulted or arched structure in the body, in particular. (Google Dictionary) 5. A triangular area of white matter in the mammalian brain between the hippocampus and the hypothalamus. (Google Dictionary) 6. Generally, any arch shaped structure (but often it refers to the arched roof of an anatomical space). (wordnetweb.princeton.edu) Word origin: From Latin fornix “arch, vaulted...
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Fossa
/ˈfäsə/ Noun (Zoology) pl. fossas 1. A mammal endemic to Madagascar (spelled ‘fosa’ in Malagasy and by some authors in English); Giant Fossa (Cryptoprocta spelea), a large, extinct mammalian predator that lived on Madagascar. (wikipedia.org) 2. The genus of the Malagasy civet. (wikipedia.org) 3. A large nocturnal reddish-brown catlike mammal of the civet family, found in the rain forests of Madagascar. (Google Dictionary) (Anatomy) pl. fossae 1. A depression or hollow in a bone or other part of the body. (wikipedia.org) 2. A pit, groove, cavity, or depression, of greater or less depth. (wiktionary.org) 3. A pit, groove, cavity, or depression, of greater or less depth; as, the temporal fossa on the side of the skull; the nasal fossae containing the nostrils in most birds. (biology-online.org) (Geology) 1. A depression on the body of an extraterrestrial body, such as a planet or moon. (wikipedia.org) 2. A long, narrow, shallow depression on the body of an extraterrestrial body, such as a planet or moon. (wiktionary.org) Word origin: From Old French fosse “ditch, grave, dungeon” (12c.), from Latin fossa “ditch,” in full fossa terra, literally “dug earth,” from fem. past participle of fodere “to...
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Fovea centralis
/ˈfōvēə/ Noun, pl. foveae Also generally known as fovea. 1. A part of the eye, located in the center of the macula region of the retina. The fovea is responsible for sharp central vision (also called foveal vision), which is necessary in humans for reading, driving, and any activity where visual detail is of primary importance. (wikipedia.org) 2. A tiny spot located in the macula that is the area of clearest vision on the retina. (biology-online.org) 3. Area consisting of a small depression in the retina containing cones and where vision is most acute. (wordnetweb.princeton.edu) Word origin: From Latin fovea (“ditch,...
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Foveola
Noun, pl. foveolas or foveolae or foveolæ (Anatomy) 1. The center of the fovea in the macula of the eye, approximately 0.35 mm in diameter, containing only cone cells. (wiktionary.org) 2. A yellowish, cone photo receptor filled portion of the human retina located within a region called the macula. The foveola is approximately 0.35 mm in diameter and lies in the center of the fovea and contains only cone cells, and a cone-shaped zone of Müller cells. (wikipedia.org) Word origin: Latin word meaning a little pit (diminutive of Latin...
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Struggling in Biology?
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Confused about the MCAT? Not sure how to prepare? This guide will show you how | {
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-441,941,291,257,835,650 | CBT Strategies
The impacts of Cognitive Behavioral Therapy differ significantly when applied to an individual and when used in a group setting (McLeod, Tully, Weisz, & Kendall, 2016). In both settings, the counselor is bound to come across challenges of which he/she must address professionally to achieve optimal final results since each case presents different forms of challenges. In this case, the family of the client who has been having suicidal thought presents challenges in the form of the hierarchical and structure of the family and lack of clear communication which may inhibit the healing process of the client.
The most effective strategies that could be applicable here is that the counselor ought to view the whole family as the client other than narrowing down to the affected client to enable comprehension of client in the context of the family system ( Knopf, 2017). By doing so, the counselor will come up with the most appropriate therapeutic interventions that will address the root cause of the problem.
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-2,578,152,753,736,975,000 | Bone health in Down syndrome
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5. Bone health in Down syndrome
Patients with Down syndrome have a number of risk factors that theoretically could predispose them to osteoporosis. In addition, the bone mass of these people may be affected by their anthropometric and body composition peculiarities. In general terms, studies in adults with Down syndrome reported that these people have lower areal bone mineral density (g/cm(2)) than the general population.
Med Clin (Barc). 2017 May 29. pii: S0025-7753(17)30352-. doi:10.1016/j.medcli.2017.04.020
Más información
García-Hoyos M, Riancho JA, Valero C
Patrocinadores de la web
Lilly
Laboratorios Rubió
Grupo Italfármaco
UCB-Pharma
Theramex
Stada
Gedeon Richter
Kyowa Kirin
Amgen
Meiji Pharma
Faes Farma | {
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5,266,412,864,219,733,000 | womensecr.com
• Sepsis( blood poisoning) symptoms
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Sepsis is a severe disease that develops when infects the blood of with pyogenic microbes or their toxins when the immune mechanisms fail. If in this case a large number of microbes are found in the blood, then this condition is called septicemia. If this condition is caused not by septicemia, but by finding in the blood only the products of their vital activity - toxins, then they talk about toxemia. If the general intoxication is accompanied by the formation of purulent foci in various tissues and organs, then this condition is called septicopyemia. Symptoms, course. High temperature with significant fluctuations and chills. Heavy general condition of the patient, frequent pulse of small filling, pronounced general weakness, sometimes pouring perspiration, exhaustion of the patient. In the blood, high leukocytosis with a significant shift of the white formula to the left. Purulent wounds become lethargic, bleed, the pus's compartment decreases, the wound becomes dry.
Treatment.
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The main purulent foci( or foci), which caused the general infection of the body, should be widely opened, treated with antiseptic substances and drained or tamponized. Absolute peace and careful care for the sick. Inside prescribe sulfanilamide preparations according to the scheme, widely used antibiotics of a wide range of action, taking into account the sensitivity of microflora to them. Enter a large number of liquids( abundant drink, IV, and / or infusion, drop enema).Concentrated, easily digestible, rich in vitamins food( milk, strong broth, egg yolks, etc.), wine( cognac, port wine, champagne), freshly brewed tea with a lot of sugar, lemon.
Prevention of .Timely and adequate treatment of various acute purulent processes. Early surgical treatment of purulent foci and antibiotics.
Septic shock is a life-threatening condition that results from the ingress of infectious viruses( sepsis) into the blood, usually bacteria. Inflammation as a response of the body to infectious agents or their toxic secretions leads to the production of substances that cause the expansion of blood vessels, a decrease in cardiac output and the infiltration of fluid from small blood vessels into tissues. Blood pressure drops sharply( septic shock), and body cells begin to experience oxygen starvation and die off.
Cell damage can quickly lead to a massive failure of organ systems - the liver, lungs, brain, kidneys and heart. The inadequacy of any of the vital organs can be fatal. Septic shock often occurs in hospitalized patients, especially with serious infectious diseases. Early detection of signs of possible shock and immediate treatment are necessary.
• Bacterial infection is the most common cause of septic shock. Stitched wounds, deep cuts, burns, surgical procedures or the use of a urinary catheter can lead to the ingress of bacteria into the blood.
• Sometimes viral or fungal infections cause a septic shock.
• Risk factors for the development of septic shock and for more serious consequences include other diseases, such as diabetes mellitus, late stage cancer and cirrhosis;severe injury or burns;serious operations;weakened immune system due to AIDS or cancer treatment. Newborns and the elderly are also at higher risk of disease.
It is observed more often in septic miscarriages, especially in later periods, less often with infected labor. It occurs mainly in cases of mass lysis of Gram-negative bacteria( Escherichia coli group, Proteus, Pseudomonas aeruginosa), endotoxin is released upon destruction of the envelope. Less commonly observed with infection caused by staphylococci or streptococci. At the heart of septic shock lie acute disorders of hemodynamics. Often accompanied by a violation of blood clotting. There is a danger of bleeding from hypo- and afibrinogenemii. Hypoxia and acidosis are expressed.
Symptoms, course. The disease begins suddenly with chills and very high fever. There are tachycardia, hyperemia, hypotension. After a few hours the blood pressure drops sharply, the pulse becomes frequent, weak filling. In the diagnosis it is important that the drop in blood pressure is not associated with bleeding. Against this background, acute renal failure may develop, manifested first oliguria( urine is released less than 400 ml per day).There are paresthesia, hypotension, a disorder of the heart activity( rhythm disturbance, brady or tachycardia, cardiac blockade), stuporosis, dyspnea, vomiting. After 5-6 days, diuresis is gradually restored, polyuria occurs.
Treatment. You should urgently call a doctor and immediately start fighting with shock. Intravenously injected plasma or plasma substitutes( polyglucin) 250-500 ml of jet, then up to 2000 ml of drip. When bleeding blood is poured. In the initial stage of shock, antihistamines and vasodilators are shown, with the collapse of norepinephrine, mezaton, hyperthesin, intravenously high doses of prednisolone( 100-200 mg, and 500-1000 mg per day).To prevent intravascular coagulation, 5000-10 000 IU of heparin is injected every 6 hours. Of the antibiotics, kanamycin, ampicillin and penicillin in high doses( up to 10,000,000 units per day).Removal of the fetal egg or uterus is possible only after removal of the patient from the shock state. In acute renal failure, urgent hospitalization in a special department( "Artificial kidney") is indicated.
Sepsis is a disease that is especially prone to newborns. The causative agent can be a variety of microorganisms and their combinations. Recently, Staphylococcus is especially often secreted. Infection is possible in utero, during childbirth and is often extra-utero. The source of infection is a sick mother;staff caring for the child may be the carrier of the infection;Important are contaminated care items, as well as the baby's food and inhaled air. The entrance gates of infection can be skin, mucous membranes, gastrointestinal tract and respiratory tract;The most frequent gateway to infection is the navel. Sepsis has no definite incubation time;with intrauterine infection it can begin on the 1st week of life, in other cases - at the 2nd and even the 3rd week. Two main forms of the disease, septicemia and septicopyemia, are distinguished along the course.
Common initial manifestations of sepsis - deterioration of well-being, sluggish sucking, regurgitation, vomiting, cessation of weight gain or slight weight loss. There may be a high fever, a low subfebrile condition and even a normal temperature. Skin with a grayish tinge.
Septicemia is more common in preterm and debilitated children, more violent, malignant. Often begins with acute intoxication, violations of water and mineral metabolism, with the development of dyspepsia, jaundice, hemorrhagic syndrome, rapid loss of weight. Tachycardia, muffling of cardiac tones, toxic respiration are observed. Sometimes symptoms of nervous system damage prevail( anxiety, frustration, convulsions).There is an increase in the liver, spleen, anemia, leukocytosis, neutrophilia, increased ESR.In the urine can be found leukocytes, red blood cells, cylinders.
Septicopyemia, ie sepsis with metastases, secondary purulent foci, proceeds more benignly, is more often observed in full-term children, with better reactivity of the organism. It begins with the appearance of pustules on the skin, sometimes abscesses develop, furuncles. Possible purulent foci in the pleura, pericardium, in the lungs, as well as purulent otitis, meningitis, etc. With umbilical sepsis in cases where the entrance collar of the infection was the navel, in addition to general phenomena, omphalitis, periarteritis of the umbilical artery and phlebitis of the umbilical vein can be observed.
Treatment of .Careful care, breastfeeding. Immediate administration of broad-spectrum antibiotics, penicillin is used in a daily dose of up to 200,000 U / kg of body weight. It is advisable to administer antibiotics at the lesion site( intrapleural, into the abscess cavity, etc.).In severe cases, a combination of antibiotics with sulfanilamide preparations is shown at a rate of 0.2 g / kg of body weight per day. Carry out stimulating therapy - direct blood transfusion, the introduction of plasma( up to 10 ml / kg of body weight every 3-4 days) and gamma globulin directed( 1.5-3 ml every other day, only 3-5 times).Corticosteroids are prescribed a short course only in the acute period of sepsis with severe general toxic effects( 1 mg / kg body weight per day).Vitamins, enzymes, local treatment of septic foci( medicamentous, surgical, physiotherapeutic) are recommended. The prognosis is favorable with timely and active treatment.
Septicemia is a septic lesion of the whole organism, in which germs, getting into the blood and multiplying in it, are carried throughout the body, causing intoxication of it. When septicopyemia germs, getting with blood flow to different organs, form in them metastatic foci of septic infection, which are usually subjected to suppuration. Symptoms, course. The disease begins on the 2nd-4th day after childbirth by a sharp increase in body temperature, increased heart rate, chills. The general condition of the puerperium is heavy. The tongue is dry, covered, the stomach is moderately swollen. Skin covers are of earthy yellow color, headache, thirst, dry mouth. Uterus flabby, poorly shortened, somewhat sensitive to palpation, significant bloody-ichoric discharge. In the urine protein, in the blood leukocytosis and elevated ESR.In the future, there may be metastatic foci in different organs. Depending on their location in the clinical picture, cardiac abnormalities predominate( myocardial damage, endocardium), respiratory organs( metastatic pneumonia), kidneys( focal nephritis).With the reverse development of the metastatic focus of infection, there is a slight improvement in the overall condition with a decrease in temperature. However, when a new foci occurs, the temperature rises again, chills appear and the symptoms caused by the damage to one or another organ.
Treatment. All medical measures should be carried out against a background of careful care for the patient( rational nutrition, abundant drink, compliance with the purity of the body).The main importance in the treatment of septicemia and septicopyemia are antibiotics prescribed in large doses( at least 6 000 000 units per day) and in different combinations. It is necessary to determine the sensitivity of microflora to antibiotics. Semisynthetic penicillins( methicillin and oxacillin), a combination of oleandomycin with tetracycline, oletetrin, and sigmamicin are effective. From sulfonamides, long-acting drugs( sulfapyridazine, sulfadimethoxin, madribon) are of great importance. It is necessary to simultaneously prescribe antifungal drugs( nystatin, levorin, decamine) in order to avoid candidiasis.
Treatment with antibiotics is combined with the administration of anatoxin, gamma globulin, blood transfusion, polyglucin infusions, hemodezia and the administration of vitamins. Treatment of sepsis is carried out only by a doctor.
Sepsis otogenous( thrombophlebitis of sigmoid sinus) complication of acute and chronic suppurative otitis media. Occurs during the transition of the inflammatory process to the wall of sigmoid, less often transverse venous sinus. As a result of infection, there is a thrombus in the sinus, which later becomes inflamed. The detached parts of a purulent thrombus can be carried by a current of blood into the lungs, joints, muscles, subcutaneous tissue, kidneys, etc.
Symptoms. Leaping temperature with an increase to 40-41 ° C, a tremendous chill and drop to normal with a torrential sweat. Less often sepsis occurs with a constant high temperature( usually in children).Heavy general condition, frequent pulse of weak filling. When a blood test is found, typical for sepsis changes.
Treatment. Operation on the ear with the opening of the sigmoid sinus and removal of the clot. Penicillin injections( 250,000 units 6-8 times a day), streptomycin( 500,000 units twice a day), sulfonamides( 6-10 g / day).In children, respectively, smaller doses. Anticoagulants( heparin, neodicumarin), cardiac agents.
Sepsis rhinogenic - a complication of acute or chronic purulent inflammation of the sinus of the nose.
Symptoms and treatment are the same as in otogenous sepsis( surgery is performed on the paranasal sinuses). | {
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3,196,780,821,654,913,500 | +1. 215.677.3060 iacdworld@yahoo.com
15th World Congress of the IACD
Dresden, Germany June 18-20, 2020
International Academy of Cosmetic Dermatology
LASER HAIR REMOVAL
Unwanted facial and body hair can be a significant problem; it can affect the way we feel, affect our social interactions, and influence what we wear and what we do. While mild hirsutism and hypertrichosis are most often physiologic, it should not be forgotten that severe hirsutism and hypertrichosis can be a clue to an underlying systemic illness. Hirsutism, especially when associated with irregular menses, acne, or female pattern hair loss, can be caused by androgen excess. Late onset hypertrichosis could also be due to other underlying problems.
There are various methods to camouflage unwanted bodily hair, e.g. plucking, shaving, bleaching, hair removal creams, or epilation. Electrolysis can result in permanent hair follicle destruction. Each follicle needs to individually treated, often repeatedly to achieve this.
Laser hair removal therapy can produce either a permanent reduction in hair density or permanent removal of unwanted hair. Permanent reduction in hair density means that some hair continue to regrow after a single course of laser therapy, and ongoing maintenance laser therapy may be needed. Permanent hair removal means that the hair never regrows even after a single course of laser therapy.
Whether a person achieves permanent hair removal rather than a permanent reduction in hair density is influenced not only by the color and thickness of the hair being treated and the color of the patient’s skin, but also by the type and quality of the laser being used and the competence and training of the person operating the laser.
Which laser and how does it work?
Lasers emit a specific monochromatic wavelength of light. When targeted on the skin, the energy from the light is transferred to a target chromophore. For hair removal, the target chromophore is melanin pigment. Energy absorbed by melanin is converted to heat that produces thermal damage to the surrounding tissue.
To achieve hair removal, the target tissues are the hair follicle stem cells in the hair bulge, which may be found at the level of insertion of the arrector pili muscle. Specific parameters are modified to enable the laser beam to selectively destroy bulge cells without damage to the bystanding tissue.
Lasers suitable for hair removal include:
• long- pulse ruby lasers
• long- pulse alexandrite lasers
• long- pulse diode lasers
• long -pulse Nd:YAG lasers
Intense pulsed light (IPL) devices are not laser devices but flash lamps that emit multiple wavebands of light simultaneously and work in a similar fashion.
To bypass epidermal melanocytes and thereby minimize the risk of consequential skin dyspigmentation, long wavelength light is required. In fair skinned people with dark hair, an IPL device, an Alexandrite laser, or a diode laser can be used. In dark skinned people with dark hair a Nd:YAG or diode laser can be employed. For blond or red hair, a diode laser can be used. For gray hairs with no melanin pigmentation, currently available lasers are ineffective. The use of pigment dyes to color gray hair prior to treatment is being studied.
To bypass hair pigment on the skin surface, hairs are carefully shaved prior to treatment. Plucking cannot be used to prepare for laser treatment, as hair shafts below the skin surface are the target chromophore. Retreatment intervals must be sufficiently long to allow new hair growth to reach the level of the bulge.
To control spread of heat and consequential thermal damage to surrounding tissue, short pulse duration is required. Repetition of laser pulses at intervals longer than the ‘thermal relaxation time’ of the surrounding tissue enables efficient target tissue destruction without heat spread.
To control the amount of heat generated in the target chromophore and surrounding tissue, the energy can be adjusted. The unit of energy is Joules/cm2. High energy produces greater bulge cell damage, but also increases the treatment discomfort experienced by the patient and the risk of laser burn.
Laser burn occurs when energy is too high, surface hair has not been removed carefully enough, or recent sun tanning (epidermal pigmentation) is not accounted for in setting the laser parameters, or when an inappropriate wavelength is employed- for example use of an Alexandrite laser in a person with a Fitzpatrick type IV or V skin.
How many treatments will I need?
1. Fitzpatrick skin types I and II:
People with dark hair can usually achieve permanent hair removal with 4-6 treatments at 4 to 6 weekly intervals. People with fair hair will generally only achieve permanent hair reduction. After an initial course of treatment, 6-12 monthly treatments may be needed.
2. Fitzpatrick skin types III:
People with dark hair can usually achieve permanent hair removal with 6-10 treatments at 4 to 6 weekly intervals. People with fair hair will generally only achieve permanent hair reduction and after an initial course of treatment may require 3-6 monthly repeat treatments.
3. Fitzpatrick skin types IV and V:
People with dark hair can usually achieve permanent hair reduction with 6-10 treatments at 4 to 6 weekly intervals. Maintenance will usually be required with 3-6 monthly repeat treatments. People with fair hair are unlikely to respond.
What side effects may occur?
You will be advised to wear goggles during the laser treatment session to prevent eye injury. There will be some pain experienced during the treatment, especially during the first few sessions. This is mainly due to incomplete hair removal prior to the procedure. Residuals hairs missed during shaving absorb laser energy and heat the skin surface producing pain. With repeat treatments at regular intervals, this occurs less often.
After the laser treatment, the skin will feel hot for 15-30 minutes. There may be redness and swelling for up to 24 hours. More serious side effects include blisters, hyper- and hypo-pigmentation, or infrequently even permanent scarring. This generally occurs when there has been recent sun-tanning, the laser settings have not been adjusted, or when patients are taking medications that affect the skin’s response to sunlight.
Rodney Sinclair, MB BS
Melbourne, Victoria, Australia | {
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-3,664,491,950,718,890,000 | Pulled muscle sign of pregnancy
Wife made pulled muscle sign of pregnancy which, you
Although vitality ranges typically rise throughout the second trimester, it's common initially of being pregnant to really feel extremely and inexplicably worn out, such as you've just run a marathon even though you only commuted to work. Slate has additionally reported on this. How they happened having youngsters; be pulled muscle sign of pregnancy through adoption, step parenting, foster care, being a single father or mother or giving birth themselves is irrelevant. We now have tried every little thing. Some ladies expertise totally different symptoms right from the beginning while other girls is not going to expertise any - even xign the confirmation from a Pregnancy check. Mood swings are also pulled muscle sign of pregnancy, especially in the first trimester. It was adopted by pgegnancy scan on this Wednesday, but every part turned out good. One lady mentioned, I had a bizarre thing where I woke and I could not breathe in or out… and that lasted about twenty minutes and made the most ghastly noise. Your breasts might pregnany feel enlarged and slightly painful, a sensation of fullness or ache in pelvis, elevated vaginal discharge and urinate frequently. But I wasn't, I wasn't that eager on it at first, I was pregancy, 'No, I do not need it'. Both approach, ensure you attempt to eat a balanced and healthy diet. Eight hours or so of shut-eye can make a world of difference. Mjscle stuck on Clomid: Docs prescribe Clomid pregnancy symptom cold feet it's thought that a girl is not ovulating; the drug stimulates the ovaries to launch an egg. If you're trying to change into pregnant, your doctor might recommend that pulled muscle sign of pregnancy just hold a document of your physique temperature every single day. Pregmancy slightly more likely to have recognizing should you've had IVFor comparable treatment, to help you conceive. Constipation will be experienced, which will also be the explanation for bizarre cramping within the lower abdomen Nagging cramps earlier than pulled muscle sign of pregnancy delay can be the symptom of inflammatory processes or simply signify the start of regular menstruation. We assessed settlement between medical pulled muscle sign of pregnancy analysis measurements utilizing the concordance and intraclass correlation coefficients, and Bland and Altman's limits of agreement. I really like how they use fruit to let you already know the place your child developmentally is at. In lots of instances ladies that experience rib ache during pregnancy also complain of shoulder ache and this is primarily as a result of pulldd that are being referred out from that area sigj the shoulders. Breasts usually develop into swollen and enlarged within the first trimester because of increased levels of the hormones pregnandy and progesterone. Such an ideal antidote to the same old fear-making stuff. Balance weight loss program is best and first ingredient to managing pregnancy conditions. Medscape's clinical reference is essentially the most authoritative and accessible level-of-care medical reference for physicians and o professionals, accessible on-line and via all major cellular devices. If you're not in a position to see puller through the fifth week pregnancy, don't be pulled muscle sign of pregnancy. I am simply entering my 7th week of my very first pregnancy, and the kuscle is annoying. This will happen once more when the infant's head drops into the pelvis before start. In case your geography isn't that sizzling, we are talking round 18 million infants. I noticed my own little Quasimobryo's heartbeat on Monday, and pumped my fists in the air and instructed my husband to get my toddler's giant melon head out of the way in which kf the display screen. If doubtful about any indicators of labor that you just're experiencing, name her up and have a chat and let her know what's taking place. Bupa Australia is just not accountable for any loss or harm you endure arising out of the usage of or reliance on the knowledge. Muscpe smoke, drink alcohol or take medicine if you are pregnant. I made a decision to go pulled muscle sign of pregnancy the doctor (in our nation, the medical doctors services are all for free, lined by social companies and when you've got any well being points, all it's important to do is present smoking during pregnancy statistics 2010 at the medical doctors office for a checkup), however took a being fo take a look at before that. Find out what's taking place with you and your child in these three levels. Areas for improvement included infant feeding and better communication in the context of individualised pulled muscle sign of pregnancy.
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Comments:
17.12.2016 at 03:04 Nikorr:
The matchless message ;)
21.12.2016 at 00:59 Fauzuru:
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14.01.2017 at 16:37 Dorg:
Yes, happens...
20.01.2017 at 04:08 Fauran:
Sometimes there are things and is worse
22.01.2017 at 09:48 Mutilar:
Without variants.... | {
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Can calories be perceived and do they affect hunger in obese and nonobese humans?
, : Can calories be perceived and do they affect hunger in obese and nonobese humans?. Journal of Comparative and Physiological Psychology 80(2): 250-258
The relation between hunger or satiety and the energy content of a meal was studied in 14 nonobese and 7 obese subjects. They were given at random a series of meals of high or low energy value at their usual breakfast or lunchtime in the form of skimmed milk flavoured with chocolate, Dexin and sweetener. This eliminated sensory cues such as taste, texture and appearance. During the baseline period of 5 to 10 days the meal supplied 0.82 and during the experimental period 1.07 or 0.57 kcal/ml.
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Meisner, Michael, 2003: Dr Meisners response. Clinica Chimica Acta 328(1-2): 201, February | {
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Article
Comparative Transcriptome-Based Mining of Genes Involved in the Export of Polyether Antibiotics for Titer Improvement
1
State Key Laboratory of Microbial Metabolism, Shanghai-Islamabad-Belgrade Joint Innovation Center on Antibacterial Resistances, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
2
Joint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai 200240, China
3
Institute of Biopharmaceuticals, Taizhou University, Taizhou 318000, China
*
Authors to whom correspondence should be addressed.
Antibiotics 2022, 11(5), 600; https://doi.org/10.3390/antibiotics11050600
Submission received: 27 March 2022 / Revised: 27 April 2022 / Accepted: 28 April 2022 / Published: 29 April 2022
(This article belongs to the Special Issue Synthetic Biology Brings New Opportunity for Antibiotics Discovery)
Abstract
:
The anti-coccidiosis agent salinomycin is a polyether antibiotic produced by Streptomyces albus BK3-25 with a remarkable titer of 18 g/L at flask scale, suggesting a highly efficient export system. It is worth identifying the involved exporter genes for further titer improvement. In this study, a titer gradient was achieved by varying soybean oil concentrations in a fermentation medium, and the corresponding transcriptomes were studied. Comparative transcriptomic analysis identified eight putative transporter genes, whose transcription increased when the oil content was increased and ranked top among up-regulated genes at higher oil concentrations. All eight genes were proved to be positively involved in salinomycin export through gene deletion and trans-complementation in the mutants, and they showed constitutive expression in the early growth stage, whose overexpression in BK3-25 led to a 7.20–69.75% titer increase in salinomycin. Furthermore, the heterologous expression of SLNHY_0929 or SLNHY_1893 rendered the host Streptomyces lividans with improved resistance to salinomycin. Interestingly, SLNHY_0929 was found to be a polyether-specific transporter because the titers of monensin, lasalocid, and nigericin were also increased by 124.6%, 60.4%, and 77.5%, respectively, through its overexpression in the corresponding producing strains. In conclusion, a transcriptome-based strategy was developed to mine genes involved in salinomycin export, which may pave the way for further salinomycin titer improvement and the identification of transporter genes involved in the biosynthesis of other antibiotics.
1. Introduction
Polyether antibiotics, also called polyether ionophores, are a broad class of natural compounds produced by actinomycetes, with the vast majority being derived from the genera Streptomyces and Actinomadura [1]. In recent years, with the discovery of over 120 novel molecules, these chemicals have received more and more attention. Typical polyether antibiotics, including salinomycin, nigericin, lasalocid, and monesin (Figure 1), feature 2–5 ether oxygen atoms and a carboxyl group [2]. This structure enables them to chelate with metal cations, such as Na+ and K+, and protons to form neutral coordination compounds, which cross the cell membrane and subsequently change ion gradients and osmotic pressures, thus resulting in cell death [1]. Salinomycin, a polyether antibiotic produced by Streptomyces albus DSM41398 and its derived strains [3], is widely applied in husbandry because it has properties that kill Gram-positive bacteria and coccidia [4]. Recent studies have found that salinomycin also inhibits the growth of leukemia stem cells [5] and epithelial cancer stem cells [6], indicating that it is a potential anti-tumor drug [6].
The high-titer Streptomyces albus strain BK3-25 produces 18 g/L salinomycin under lab conditions [7], but the intracellular accumulation of salinomycin poses a threat to cell growth, which can be released by the strain’s resistance ability [8,9,10]. However, the mechanism underlying this antibiotic resistance remains elusive. According to our previous work, SLNHY_261 (slnTII) and SLNHY_262 (slnTI) in a salinomycin biosynthetic gene cluster (BGC), encoding the ATP-binding subunit and transmembrane subunit, respectively [11], were thought to form an ATP-binding cassette (ABC) complex participating in salinomycin export. When slnTI and slnTII were deleted in Streptomyces albus XM 211, the salinomycin titers of the corresponding mutants declined by only 27.2% and 45.4%, respectively [12], indicating that there are additional genes involved in salinomycin export, which may be located beyond the salinomycin BGC regions.
Actinomycetes have large-capacity transporter protein systems, which participate in cell metabolism, intercellular communication, biosynthesis, and proliferation [13]. The ABC superfamily [14] and major facilitator superfamily (MFS) [15] are two well-studied classes of transporters. Whole-genome sequencing has illustrated that there are numerous ABC and MFS transporter genes in an actinomycetal genome both inside and outside of secondary metabolite BGCs [13,16]. Wang et al. analyzed transcriptome expression differences with expression profile chips and discovered 13 candidate transporter genes outside the natamycin BGC from Streptomyces chattanoogensis L10 [17]. Chu et al. built a step-by-step workflow based on the TCDB database BLAST, and they included substrate analysis, transporter classification analysis, and phylogenetic analysis to mine BGC-independent exporters. Together with a tunable plug-and-play exporter module with replaceable promoters and ribosome-binding sites, they realized the titer improvement of macrolide biopesticides in different Streptomyces producers [18]. Nevertheless, the current commonly used approaches are mainly sequence-dependent or based on known exporters, and the methods of BGC-independent exporter mining still need development.
Soybean oil serves as the main carbon source in salinomycin fermentation, supplying energy through primary metabolism and precursors, such as malonyl-CoA, methylmalonyl-CoA, and ethylmalonyl-CoA, for salinomycin biosynthesis. Usually, 15% (w/v) of soybean oil is added to the fermentation medium, which is extremely high compared with other antibiotic fermentations. Our previous work revealed that increased soybean oil addition resulted in higher salinomycin production [19], and, thus, we hypothesized that higher concentrations of soybean oil cause a higher transcription of exporter genes.
Herein, a strategy based on comparative transcriptomic analysis under different concentrations of soybean oil supplementation was developed to identify salinomycin exporter genes (Figure S1, Supporting Information). Our work provided universal exporters for the titer improvement of polyether antibiotics in Streptomyces. Furthermore, our method might broaden transporter engineering toolkits for the titer improvement of other valuable products in Streptomyces.
2. Materials and Methods
2.1. Strains, Plasmids, and Culture Conditions
The bacterial strains and plasmids used in this study are listed in Table S1, Supporting Information.
S. albus BK3-25 (from Zhejiang Shenghua Biok Biology Co., Ltd., Deqing, China) and its mutants were grown on ISP4 medium (10 g/L soluble starch, 2 g/L (NH4)2SO4, 1 g/L K2HPO4, 2 g/L CaCO3, 1 g/L NaCl, 1 g/L MgSO4, 100 μL of trace element solution (1% ZnSO4, 1% MnCl2, 1% FeSO4 (w/v)), 20 g/L agar) for 7 days for sporulation. The conjugation of Streptomyces with Escherichia coli was carried out on ISP4 plates supplemented with 20 mM MgCl2. The fermentation procedure was as follows: S. albus BK3-25 and its mutants were grown in 30 mL of TSBY medium [20] (30 g/L tryptone soya broth, 5 g/L yeast extract, 103 g/L sucrose) at 30 °C and 220 r.p.m. for 48 h. Then, 1 mL of the culture was transferred into 30 mL of the seed medium (30 g/L soybean meal, 10 g/L yeast extract, 2 g/L CaCO3, 80 mL/L 50% glucose) and cultivated at 33 °C and 220 r.p.m. for 16 h. Finally, 5 mL of the seed culture was transferred into 50 mL of the fermentation medium (8 g/L germ powder, 5 g/L soybean meal, 2.2 g/L KCl, 1 g/L NaCl, 1.6 g/L urea, 2 g/L tartaric acid, 0.1 g/L MgSO4, 0.1 g/L K2HPO4, 5 g/L CaCO3, pH 6.6–6.9, supplemented with 7.5 g/50 mL soybean oil) and cultured at 33 °C and 220 r.p.m. for 9 days [11].
S. lividans TK24, S. cinnamonensis ATCC 15413, S. lasaliensis ATCC 31180, S. hygroscopicus XM201-ga32 and their mutants were grown on SFM medium (20 g/L soybean meal, 20 g/L mannitol, 20 g/L agar) for 7 days for sporulation. The conjugation of Streptomyces with E. coli was carried out on SFM plates supplemented with 20 mM MgCl2.
For fermentation, S. cinnamonensis ATCC 15413 and its mutants were grown in 25 mL of the seed medium (20 g/L dextrin, 15 g/L soybean meal, 2.5 g/L yeast extract, 5 g/L glucose, 1 g/L CaCO3, pH 6.7–6.8), and then 2.5 mL of the seed culture was transferred into 25 mL of the fermentation medium (20 g/L soybean oil, 45 g/L glucose, 40 g/L soybean meal, 2.2 g/L NaNO3, 2.2 g/L Na2SO4, 0.07 g/L Al2(SO4)3, 0.1 g/L FeSO4, 0.33 g/L MnCl2, 0.075 g/L K2HPO4, 2.5 g/L CaCO3, pH 6.7–6.8) and cultured at 32 °C and 250 r.p.m. for 10 days.
S. lasaliensis ATCC 31180 and its mutants were grown in 25 mL of the seed medium (20 g/L sucrose, 20 g/L soybean meal, 5 g/L tryptone, 5 g/L malt extract, 2 g/L NaCl, 4 g/L CaCO3, pH 7.0), and then 2.5 mL of the seed culture was transferred into 25 mL of the fermentation medium (5 g/L glucose, 40 g/L dextrin, 35 g/L soybean meal, 7.5 g/L corn starch, 3 g/L NaCl, 4 g/L KH2PO4, 2 g/L MgSO4·7H2O, pH 7.0) and cultured at 28 °C and 200 r.p.m. for 6 days [21].
S. hygroscopicus XM201-ga32 and its mutants were grown in 50 mL of the seed medium (10 g/L glucose, 10 g/L tryptone, 5 g/L yeast extract), and then 7.5 mL of the seed culture was transferred into 50 mL of the fermentation medium (30 g/L corn starch, 70 g/L glucose, 40 g/L soybean meal, 3 g/L (NH4)2SO4, 0.01 g/L CoCl2, 10 g/L CaCO3, 1 g/L soybean oil, pH 6.8–7.0) and cultured at 30 °C and 220 r.p.m. for 7 days [22].
E. coli ET12567 (pUZ8002) was used for conjugation. The E. coli cells were cultured in Luria–Bertani (LB) broth at 37 °C.
2.2. Transcriptome Sequencing of BK3-25
For transcriptome sequencing, mycelia were harvested on the third day of fermentation. The total RNA was extracted using Redzol according to the manufacturer’s instructions. Transcriptome sequencing was performed by the Shanghai Biotechnology Corporation, and the expression level of each gene was calculated as fragments per kilobase of exon per megabase of library size (FPKM).
2.3. Construction of Plasmids for Deletion and Over-Expression of Eight Candidate Genes
For gene deletion through homologous recombination, left and right flanking regions of each gene were obtained using PCR amplification, ligated to EcoRV-digested pBluescript SK, and sequenced (Figure S2A). Then, these plasmids were digested with XbaI/EcoRI or EcoRI/HindIII and ligated to XbaI/HindIII-digested plasmid pJTU1278. The primers used for gene deletion are listed in Table S2.
For gene overexpression, eight candidate genes were obtained using PCR amplification, ligated to EcoRV-digested pBluescript SK, and sequenced. Then, these plasmids were digested with XbaI/NotI (NdeI/EcoRI), and the fragments containing genes were ligated with the XbaI/NotI-digested plasmid pIB139 or NdeI/EcoRI-digested plasmid pLQ646 (Figure S2B,C). The primers used for gene over-expression are listed in Table S2.
2.4. Conjugation between Streptomyces and E. coli
All the plasmids were successively introduced into the non-methylating E. coli strain ET12567 (pUZ8002) and S. albus strains. Spores (~109 CFU) were heat-shocked at 50 °C for 10 min, pregerminated for 2.5 h, and then mixed with E. coli cells. The suspensions were spread onto non-selective plates containing ISP4 medium supplemented with 20 mM MgCl2. Apramycin was overlaid on the plates after 17 h of incubation at 30 °C, and exconjugants typically appeared after 3 days.
For gene deletion, the exconjugants were assessed as single-crossover mutants using PCR amplification with primers SLNHY_X-YZ-F/R (Table S2). After two rounds of sporulation without antibiotic selection, double-crossover mutants were verified using PCR with primers SLNHY_X-YZ-F/R (Table S2 and Figure S2A). For gene over-expression, the exconjugants were verified using PCR with primers pIB139-over-YZ-F (pLQ648-over-YZ-F) and SLNHY_X-over-YZ-R (Table S2).
2.5. HPLC Analysis of Antibiotics
For the detection of total salinomycin, 1 mL of fermentation broth was mixed with 9 mL of methanol, followed by sonication at 40 kHz for 30 min. Then, 1 mL of the mixture was taken and centrifuged at 12,000 r.p.m. for 1 min, and the supernatant was filtrated and subjected to HPLC analysis. For the detection of intracellular salinomycin, 1 mL of the fermentation broth was centrifuged at 12,000 r.p.m. for 5 min, and the supernatant was discarded. The mycelia were washed twice with water and mixed with 1 mL of methanol, followed by sonication at 40 kHz for 30 min. Then, the mixture was centrifuged at 12,000 r.p.m. for 5 min, and the supernatant was filtrated and subjected to HPLC analysis. HPLC was performed on Agilent series 1260 (Agilent Technologies, Santa Clara, CA, USA) with an Agilent TC-18 column (2.1 × 150 mm, 5 μm). In this process, 8% A (water, 2% acetic acid) and 92% B (acetonitrile) were used as the mobile phase with a flow rate of 1 mL/min, and the detection time was 20 min using UV spectroscopy at 210 nm [11]. The concentrations of salinomycin were calculated according to the standard curve of salinomycin (Figure S3).
For the detection of lasalocid, 1 mL of fermentation broth was mixed with 1 mL of methanol, followed by sonication at 40 kHz for 30 min. Then, the mixture was centrifuged at 12,000 r.p.m. for 1 min, and the supernatant was filtrated and subjected to HPLC analysis. HPLC was performed on Agilent series 1260 (Agilent Technologies, USA) with an Agilent TC-18 column (2.1 × 150 mm, 5 μm) at 40 °C. In this process, 15% A (water, 0.125 mol/L ammonium acetate, pH 4.8) and 85% B (acetonitrile) were used as the mobile phase with a flow rate of 1 mL/min, and the detection time was 20 min using UV spectroscopy at 305 nm [21]. The concentrations of lasalocid were calculated according to the standard curve of lasalocid (Figure S4).
For the detection of monensin, 1 mL of fermentation broth was centrifuged at 12,000 r.p.m. for 5 min, and the supernatant was discarded. The mycelia were washed twice with water and mixed with 1 mL of ethanol, followed by sonication at 40 kHz for 30 min. Then, the mixture was centrifuged at 12,000 r.p.m. for 5 min, and the supernatant was filtrated and subjected to HPLC analysis. HPLC was performed on Agilent series 1260 (Agilent Technologies, Santa Clara, CA, USA) with an Agilent TC-18 column (2.1 × 150 mm, 5 μm). In this process, 20 mM ammonium acetate and methanol were used as the mobile phase with a flow rate of 1 mL/min. For 0–25 min, the ratio of methanol increased from 80% to 100%, and for 25–30 min, it decreased from 100% to 80%. Evaporative light-scattering detection (ELSD) was conducted for 30 min at 85 °C [23]. The concentrations of monensin were calculated according to the standard curve of monensin (Figure S5).
For the detection of nigericin, 1 mL of fermentation broth was mixed with 9 mL of methanol, followed by sonication at 40 kHz for 30 min. Then, 1 mL of the mixture was taken and centrifuged at 12,000 r.p.m. for 1 min, and the supernatant was filtrated and subjected to HPLC analysis. HPLC was performed on Agilent series 1260 (Agilent Technologies, USA) with an Agilent TC-18 column (2.1 × 150 mm, 5 μm). A gradient elution (1 mL/min flow rate) was performed using A (methanol/water, 9:1 ratio, 0.1% TFA from 0 to 25 min) and B (methanol, 100%, 0.1% TFA, from 25 to 50 min). ELSD detection was conducted for 50 min at 85 °C [24]. The concentrations of nigericin were calculated according to the standard curve of nigericin (Figure S6).
2.6. RNA Extraction and RT-qPCR Analysis
Mycelia of S. albus BK3-25 were harvested, and the total RNA was extracted using Redzol according to the manufacturer’s instructions (SBS Genetech, Shanghai, China) [25]. The quality of the RNA was determined using a NanoDrop 2000 spectrophotometer. For RT-qPCR experiments, total RNA was reversely transcribed into cDNA using RevertAidTM H Minus First Strand cDNA Synthesis Kit (Thermo Fisher, Waltham, MA USA). The RT-qPCR experiments were carried out on a 7500 Fast Real-time RCR system (Applied Biosystems, Waltham, MA USA) using MaximaTM SYBR Green/ROX qPCR Maxter Mix (Thermo Fisher, Waltham, MA USA) according to the manufacturer’s procedure. The expression values of the target genes were calculated using 2−ΔΔCT methods with the housekeeping gene hrdB as internal control [26].
2.7. Biomass Determination under Fermentation Condition
Due to the insoluble residues in the liquid medium, total intracellular nucleic acid rather than dry cell weight was determined to represent the growth of Streptomyces. The concentration of intracellular nucleic acid was detected as follows: 1 mL fermentation broth was centrifuged and washed twice to eliminate the interference of the medium. Then, 1 mL of Solution A (1.5 g diphenylamine, 100 mL acetic acid, 1.5 mL concentrated sulfuric acid, 1 mL 1.6% acetaldehyde) was mixed with the mycelia and put in water bath at 60 °C for 1 h. Then, the mixture was centrifuged, and 150 μL of supernatant was transferred into 96-well plates and detected at 595 nm (Infinite M200 PRO, TECAN, Männedorf, Switzerland).
3. Results
3.1. Transcriptome-Based Identification of Candidate Exporter Genes
We initially assumed that the higher the salinomycin titer, the higher the transcription of the involved exporter genes. In order to establish a titer gradient, different concentrations of soybean oil (5%, 10%, and 15%) were supplemented to the fermentation broth, and the corresponding salinomycin titers were 5.30 g/L, 12.50 g/L, and 17.40 g/L, respectively. Using these three samples, transcriptomic data were collected using RNA-seq technology. According to the hypothetic concurrent relationship between salinomycin titers and the transcription of exporter genes, eight exporter genes with increasing expression patterns and that topped the fold-change of transcription at a higher salinomycin titer were selected from 248 ABC transporter genes and 23 MFS genes in the BK3-25 genome. These eight genes include seven ABC transporter genes, SLNHY_3363, SLNHY_4037, SLNHY_6316, SLNHY_6652, SLNHY_0818, SLNHY_0199, and SLNHY_1893, and one MFS gene, SLNHY_0929 (Figure 2 and Table S3). Although the transcriptions of SLNHY_3363 and SLNHY_0199 at 15% oil supplementation were lower than those at 10%, both of their transcriptions dramatically rose when the oil contents were shifted from 5% to 10%.
In order to verify the transcriptomic data, the transcription levels of the eight candidate genes were measured using RT-qPCR with cultures collected on the third day of fermentation supplemented with 5% or 15% soybean oil, and all genes showed higher expressions with 15% oil supplementation, which was consistent with the transcriptomic data. Among them, SLNHY_929 demonstrated the highest expression, followed by SLNHY_3363 and SLNHY_1893 (Table S4).
3.2. All Eight Candidate Genes Were Positively Involved in Salinomycin Export
To investigate whether these eight genes are involved in salinomycin production, they were knocked out through homologous recombination. As shown in Figure 3A,B, the total salinomycin titers of all mutants decreased to 11.62–27.36% of that of BK3-25, and the intracellular concentrations of salinomycin increased to 143.61–237.89% of that of BK3-25, indicating that these genes were positively related to salinomycin biosynthesis. Moreover, the deletion of ΔSLNHY_0199 was the most pronounced, with a dramatic decrease in the salinomycin titer from 13.34 g/L to 1.55 g/L.
Further verification of the above conclusion was conducted through trans-complementation of each mutant with the corresponding gene cloned under the control of PermE*. All individually complemented strains returned to 78.77–88.77% of the original titer of salinomycin (Figure 3C), and the intracellular accumulations of salinomycin synchronically returned to 62.36–105.19% of the level of BK3-25 (Figure 3D), providing more proof of the involvement of these eight genes in salinomycin biosynthesis and, most likely, in its export.
In addition, these eight genes were individually over-expressed in BK3-25 to see whether they played vital roles in salinomycin titer improvement. As expected, compared with the control strain bearing the empty vector pIB139, the excessive expression of these genes all increased salinomycin titers by 7.20–69.75%, especially BK3-25::SLNHY_3363 and BK3-25::SLNHY_0929, which had improved titers of 24.60 g/L and 22.85 g/L, respectively (Figure 3E). Accordingly, the intracellular salinomycin accumulations of all mutants showed a marked fall to 24.35–46.23% of the same level of BK3-25 (Figure 3F).
3.3. These Eight Exporter Genes Were Constitutively Expressed
In order to determine whether the expressions of these eight genes were constitutive or induced by salinomycin, the transcription profiles of each gene were obtained using RT-qPCR with samples collected each day during the whole fermentation period (Figure 4). Compared with the house-keeping gene hrdB, these exporter genes were actively transcribed at the very beginning and then gradually decreased along with the fermentation process. Since salinomycin obviously accumulated after the first day, as shown in Figure S7, we can safely draw the conclusion that these genes were constitutively expressed rather than being induced by salinomycin.
3.4. SLNHY_0929 and SLNHY_1893 Improved Resistance to Salinomycin in Streptomyces lividans
Even though these eight exporter genes were proved to be involved in salinomycin export, we still needed to determine why they functioned in this way. Streptomyces lividans TK24 was found to be susceptible to high concentrations of salinomycin, and the minimal inhibition concentration (MIC) was 0.5 mmol/L for the control strain TK24::pIB139. These eight genes were individually introduced into S. lividans TK24. Although most mutants carrying the introduced exporter genes maintained similar susceptibility to salinomycin, TK24::SLNHY_0929 and TK24::SLNHY_1893 rendered the host with an improved resistance as high as 1.0 mmol/L (Figure 5A,B). These data strongly suggest the salinomycin export ability of SLNHY_0929 and SLNHY_1893, which exported the assimilated exogenous salinomycin out of S. lividans TK24.
3.5. SLNHY_0929 Was a Universal Exporter for Polyether Antibiotics with Similar Structure with Salinomycin
Since most polyether antibiotics shared similar hydrophobic structures, we wondered whether the exporter genes were universal in pumping them out and whether the genes played roles in improving their titers. Therefore, the three exporter genes with the most substantial effects on salinomycin titers when over-expressed in BK3-25, i.e., SLNHY_0929, SLNHY_3363 and, SLNHY_4037, were heterologously expressed in Streptomyces lasaliensis ATCC 31180 (a lasalocid producer), Streptomyces cinnamonensis ATCC 15413 (a monensin producer), and Streptomyces hygroscopicus XM201-ga32 (a nigericin producer). Herein, the previously used PermE* promoter was replaced by a stronger promoter kasOp*, since the latter was reported to work better in XM201 [22,27].
Interestingly, the heterologous expression of SLNHY_0929 resulted in a significant improvement in all three antibiotics, with lasalocid titers from 163.60 mg/L to 262.50 mg/L in S. lasaliensis (Figure 6A), monensin titers from 572.40 mg/L to 1,286.00 mg/L in S. cinnamonensis (Figure 6B), and nigericin titers from 116.77 mg/L to 207.27 mg/L in S. hygroscopicus (Figure 6C). Surprisingly, the heterologous expressions of SLNHY_3363 and SLNHY_4037 had no positive effects on the production of these three polyether antibiotics, even with unexpected, dropped titers, and the reason needed further exploration. Overall, these results clearly show that SLNHY_0929 is a universal exporter for salinomycin, lasalocid, monensin, and nigericin, which shared similar molecular structures.
Transporter engineering has been considered as a promising strategy to maximize secondary metabolite production in bacterial hosts, such as Streptomyces spp. and Aspergillus spp. [28,29]. Except for the exporters located in BGCs, BGC-independent exporters caused by horizontal gene transfer may also contribute to metabolite export [30,31]. To discover transporter genes located far from BGCs, expression profiling, genome-wide knockout studies, stress-based selection, and the inhibitor strategy have often been used [32].
Herein, due to Streptomyces albus’ highly efficient utilization of soybean oil, we found that salinomycin production rose as oil addition rose, and the transcription levels of the genes involved in salinomycin PKS, β-oxidation, and precursor biosynthesis also increased [7]. Since transporters are the essential channels of both precursor import and salinomycin export, they are more necessary with the rise in ionophore product synthesis, so we decided to focus on the study of transporters. Next, we managed to mine eight transporter genes outside salinomycin BGC based on comparative transcriptome data under different salinomycin titers. Furthermore, all eight selected genes proved to be correlated with salinomycin synthesis by gene deletion and over-expression. Among the eight genes, only SLNHY_0929 and SLNHY_1893 encoded proteins that could pump salinomycin out of the cell and, thus, provide self-resistance to the host, according to the heterologous expression in the model strain S. lividans and the salinomycin supplement experiments. Our work constructed a novel method for antibiotic transporter gene mining. The fermentation characteristics of Streptomyces albus with a soybean oil preference were focused and combined with transcriptome sequencing technology, which showed a very successful titer improvement of salinomycin through exporter engineering and might apply to other antibiotics with oil-derived precursors. Therefore, this study also provides an application with great potential in promoting the more cost-effective production of salinomycin and other chemicals.
MFS-type transporters are channels of multiple substrates, such as monose, polysaccharides, amino acids, polypeptides, vitamins, cofactors, secondary metabolites, chromophores, and bases. They can either function independently or cooperate with ABC transporters in metabolite efflux [17]. In our work, the MFS family gene, SLNHY_0929, was heterologously expressed in the producers of other polyether antibiotics, and it showed a broad spectrum of substrate identification, whose protein pumped out intracellular salinomycin, lasalocid, monensin, and nigericin, as well as increasing the titers of each. As a matter of fact, S. cinnamonensis ATCC 15413 possesses a homolog of the exporter gene SLNHY_0929, namely, orf6552, with 93% coverage and 75.81% identity, while none of the homolog is present in S. lasaliensis ATCC 31180 or S. hygroscopicus XM201-ga32. Thus, ORF6552 is considered to be an endogenous MFS transporter, which exports monensin from the host. Whether or not it served as another universal ionophore pump remains to be explored. Compared to specific exporters slnTI and slnTII in the gene cluster, SLNHY_0929 contributed more to salinomycin biosynthesis [12]. Meanwhile, endogenous exporters in lasalocid, monensin, and nigericin BGCs, which provide self-resistance to producing strains, have been reported. Lsd5 in S. lasaliensis showed 53% identity with MonT in S. cinnamonensis, and in S. hygroscopicus, R14/R15 formed an ABC transporter with 71% and 49% identities with the TMD and NBD of the transporter in S. avermitilis’s BGC, respectively [33,34,35,36]. Until now, there have been no data about these self-exporters’ functions on antibiotic production, so we could not compare them with the non-specific exporter SLNHY_0929. However, introducing this MFS transporter improved the polyether antibiotics’ titers by over 60% and almost doubled monensin’s titer, which demonstrates the efficacy of our method for transporter mining. Due to the constitutive expression of these exporter genes, we can safely draw the conclusion that SLNHY_0929 served as a universal and stable pump by flexibly identifying polyether compounds. Whether or not it could recognize other types of chemicals remains unknown. SLNHY_1893, SLNHY_3363, SLNHY_4037, SLNHY_0199, SLNHY_0818, SLNHY_6316, and SLNHY_6652 all belong to ABC transporters; however, they cannot export salinomycin according to the MIC results implemented in Streptomyces lividans. Their functions were speculated to be importers of soybean oil or other small nutrient molecules, or exporters of other secondary metabolites, such as actinopyranone and elaiophylin, whose BGCs were detected in the S. albus genome. Hence, on the one hand, in a future study, intracellular acyl-CoA concentrations will be detected to study whether these proteins pump fatty acids and glycerol derived from soybean oil [37]. On the other hand, we would like to strengthen or weaken the expression of these pumps and observe the production of possible metabolites to identify the pumps’ function.
Additionally, since each transporter exported salinomycin and improved its biosynthesis, it would be interesting to examine whether these pumps are competitive or cooperative. Thus, tandem over-expression of two or more genes will be employed to study their relationship, which may push the salinomycin titer to a higher level. By means of electronic microscope observation and molecular dynamics simulation, the conformation change of transporters during the pumping of salinomycin will be analyzed. Besides export, other resistance strategies, including the inactivation of antibiotics and the modification of function targets, are worthy of study with regard to salinomycin. Further bioinformatic and functional analyses are likely to provide answers to these questions.
4. Conclusions
In summary, we constructed a novel method for salinomycin exporter mining by combining soybean oil preference and transcriptome analysis. We identified eight BGC-independent transporters and verified their functions. Finally, one of them was proved to be efficient in multiple polyether antibiotic-producing hosts. Our work contributes new strategies to further the improvement of salinomycin titers, and it paves the way for increasing the titers of other antibiotics through transporter engineering.
Supplementary Materials
The following are available online at https://www.mdpi.com/article/10.3390/antibiotics11050600/s1, Table S1: Strains and plasmids used in this study; Table S2: Primers used in this study; Table S3: Transcription data and annotation of eight candidate genes; Table S4: RT-qPCR analysis of candidate genes; Figure S1: Flowchart of the strategy for exporter gene identification; Figure S2: The process of gene deletion and over-expression of SLNHY_0929; Figure S3: HPLC analysis of salinomycin in the fermentation cultures of BK3-25 and mutant LX01 with SLNHY_0929 deleted; Figure S4: HPLC analysis of lasalocid in the fermentation culture of S. lasaliensis and its mutants; Figure S5: HPLC analysis of monensin in the fermentation culture of S. cinnamonensis and its mutants; Figure S6: HPLC analysis of nigericin in the fermentation culture of S. hygroscopicus and its mutants; Figure S7: Growth (A) and salinomycin titer (B) curves of Streptomyces albus BK3-25. References [38,39,40,41,42,43] are cited in the supplementary materials.
Author Contributions
Conceptualization, L.B. and Y.Y.; methodology, X.L., Y.W. and X.Z.; validation, X.L.; formal analysis, L.B. and Q.K.; investigation, X.L.; data curation, L.B.; writing—original draft preparation, X.L.; writing—review and editing, L.B. and Y.Y.; supervision, L.B. and Y.Y.; project administration, L.B.; funding acquisition, L.B. and Y.Y. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by the National Key R&D Program of China (2021YFC2100600, 2019YFA0905400), the Science and Technology Commission of Shanghai Municipality (19430750600, 19JC1413000), and the National Natural Science Foundation of China (31830104, 31801036).
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Not applicable.
Acknowledgments
We thank Weishan Wang for providing the kasOp* promoter and Yongquan Li for providing the BK3-25 strain.
Conflicts of Interest
The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
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Figure 1. Structures of polyether antibiotics.
Figure 1. Structures of polyether antibiotics.
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Figure 2. (A) Salinomycin titers under 0, 5, 10, and 15% soybean oil supplementation. (B) Transcription profiles of eight candidate transporter genes under 5, 10, and 15% (w/v) soybean oil supplementation.
Figure 2. (A) Salinomycin titers under 0, 5, 10, and 15% soybean oil supplementation. (B) Transcription profiles of eight candidate transporter genes under 5, 10, and 15% (w/v) soybean oil supplementation.
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Figure 3. Salinomycin production of exporter gene mutants. (A) Total salinomycin titers of gene deletion mutants of BK3-25. (B) Intracellular salinomycin concentrations of gene deletion mutants. (C) Total salinomycin titers of gene complement mutants. (D) Intracellular salinomycin concentrations of gene complement mutants. (E) Total salinomycin titers of gene over-expression mutants. (F) Intracellular salinomycin concentrations of gene over-expression mutants. The total salinomycin titers were calculated based on the fermentation broth volume (A,C,E), and the intracellular salinomycin concentrations were calculated based on the dry cell weight (B,D,F). LX01, BK3-25ΔSLNHY_0929; LX02, BK3-25ΔSLNHY_1893; LX03, BK3-25ΔSLNHY_3363; LX04, BK3-25ΔSLNHY_4037; LX05, BK3-25ΔSLNHY_0199; LX06, BK3-25ΔSLNHY_0818; LX07, BK3-25ΔSLNHY_6316; LX08, BK3-25ΔSLNHY_6652.
Figure 3. Salinomycin production of exporter gene mutants. (A) Total salinomycin titers of gene deletion mutants of BK3-25. (B) Intracellular salinomycin concentrations of gene deletion mutants. (C) Total salinomycin titers of gene complement mutants. (D) Intracellular salinomycin concentrations of gene complement mutants. (E) Total salinomycin titers of gene over-expression mutants. (F) Intracellular salinomycin concentrations of gene over-expression mutants. The total salinomycin titers were calculated based on the fermentation broth volume (A,C,E), and the intracellular salinomycin concentrations were calculated based on the dry cell weight (B,D,F). LX01, BK3-25ΔSLNHY_0929; LX02, BK3-25ΔSLNHY_1893; LX03, BK3-25ΔSLNHY_3363; LX04, BK3-25ΔSLNHY_4037; LX05, BK3-25ΔSLNHY_0199; LX06, BK3-25ΔSLNHY_0818; LX07, BK3-25ΔSLNHY_6316; LX08, BK3-25ΔSLNHY_6652.
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Figure 4. Transcription profiles of eight exporter genes. Line with black circle, hrdB; orange square, SLNHY_0929; green equilateral solid triangle, SLNHY_1893; blue circle, SLNHY_3363; red equilateral hollow triangle, SLNHY_4037; earthy yellow hollow square, SLNHY_0199; brown inverted solid triangle, SLNHY_0818; pink inverted hollow triangle, SLNHY_6316; dark green rhombus, SLNHY_6652. Logarithm of transcription data were taken as ordinate; if not, it would be difficult to show their wide fluctuation scales.
Figure 4. Transcription profiles of eight exporter genes. Line with black circle, hrdB; orange square, SLNHY_0929; green equilateral solid triangle, SLNHY_1893; blue circle, SLNHY_3363; red equilateral hollow triangle, SLNHY_4037; earthy yellow hollow square, SLNHY_0199; brown inverted solid triangle, SLNHY_0818; pink inverted hollow triangle, SLNHY_6316; dark green rhombus, SLNHY_6652. Logarithm of transcription data were taken as ordinate; if not, it would be difficult to show their wide fluctuation scales.
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Figure 5. Biomass profiles of S. lividans TK24 mutants under different concentrations of salinomycin. Total intracellular nucleic acid was determined to represent the growth of S. lividans. (A) Green column, TK24::pIB139; orange column, TK24::SLNHY_3363; gray column, TK24::SLNHY_4037; yellow column, TK24::SLNHY_0929; blue column, TK24::SLNHY_1893. (B) Green column, TK24::pIB139; orange column, TK24::SLNHY_0199; gray column, TK24::SLNHY_0818; yellow column, TK24::SLNHY_6316; blue column, TK24::SLNHY_6652.
Figure 5. Biomass profiles of S. lividans TK24 mutants under different concentrations of salinomycin. Total intracellular nucleic acid was determined to represent the growth of S. lividans. (A) Green column, TK24::pIB139; orange column, TK24::SLNHY_3363; gray column, TK24::SLNHY_4037; yellow column, TK24::SLNHY_0929; blue column, TK24::SLNHY_1893. (B) Green column, TK24::pIB139; orange column, TK24::SLNHY_0199; gray column, TK24::SLNHY_0818; yellow column, TK24::SLNHY_6316; blue column, TK24::SLNHY_6652.
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Figure 6. Production of polyether antibiotics with heterologous expressions of exporters in other Streptomyces hosts. (A) Lasalocid production of S. lasaliensis mutants. (B) Monensin production of S. cinnamonensis mutants. (C) Nigericin production of S. hygroscopicus mutants. pLQ646, integrative vector with kasOp* promoter.
Figure 6. Production of polyether antibiotics with heterologous expressions of exporters in other Streptomyces hosts. (A) Lasalocid production of S. lasaliensis mutants. (B) Monensin production of S. cinnamonensis mutants. (C) Nigericin production of S. hygroscopicus mutants. pLQ646, integrative vector with kasOp* promoter.
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Liu, X.; Wu, Y.; Zhang, X.; Kang, Q.; Yan, Y.; Bai, L. Comparative Transcriptome-Based Mining of Genes Involved in the Export of Polyether Antibiotics for Titer Improvement. Antibiotics 2022, 11, 600. https://doi.org/10.3390/antibiotics11050600
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Liu X, Wu Y, Zhang X, Kang Q, Yan Y, Bai L. Comparative Transcriptome-Based Mining of Genes Involved in the Export of Polyether Antibiotics for Titer Improvement. Antibiotics. 2022; 11(5):600. https://doi.org/10.3390/antibiotics11050600
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Liu, Xian, Yuanting Wu, Xiaojie Zhang, Qianjin Kang, Yusi Yan, and Linquan Bai. 2022. "Comparative Transcriptome-Based Mining of Genes Involved in the Export of Polyether Antibiotics for Titer Improvement" Antibiotics 11, no. 5: 600. https://doi.org/10.3390/antibiotics11050600
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4,920,125,689,881,187,000 | Home » Frequently asked Questions on Health » How can I quit chewing tobacco?
How can I quit chewing tobacco?
Q: I am a 35 years old male addicted to tobacco chewing for the last 18 years. I got married two years back and also have a daughter. I tried quitting tobacco but whenever I start to leave, I feel extremely angry, disturbed and very insecure. I feel that I unable to sexually satisfy my wife. My friends have told me that my sexual weakness is due to chewing tobacco. I also suffer from respiratory problems. I sneeze and sweat a lot. Am I suffering from some nervous problem? What should I have to do besides leaving my tobacco habit?
A:Tobacco addiction and dependence in any form is associated with a number of physical and psychological impacts and the same is true for withdrawal/craving when somebody wants to quit consuming tobacco. There is medical help available both in the form of physician/psychiatrist/psychologist who will provide you proper guidance as well as medication to prevent withdrawal symptoms. If you are motivated enough now, it is a good time to seek medical assistance and quit.
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-6,936,010,905,762,924,000 | Partial ORF1ab Gene Target Failure with Omicron BA.2.12.1.
TitlePartial ORF1ab Gene Target Failure with Omicron BA.2.12.1.
Publication TypeJournal Article
Year of Publication2022
AuthorsRodino KG, Peaper DR, Kelly BJ, Bushman F, Marques A, Adhikari H, Tu ZJin, Rolon RMarrero, Westblade LF, Green DA, Berry GJ, Wu F, Annavajhala MK, Uhlemann A-C, Parikh BA, McMillen T, Jani K, N Babady E, Hahn AM, Koch RT, Grubaugh ND, Rhoads DD
Corporate AuthorsYale SARS-CoV-2 Genomic Surveillance Initiative
JournalmedRxiv
Date Published2022 Apr 28
Abstract
Mutations in the viral genome of SARS-CoV-2 can impact the performance of molecular diagnostic assays. In some cases, such as S gene target failure, the impact can serve as a unique indicator of a particular SARS-CoV-2 variant and provide a method for rapid detection. Here we describe partial ORF1ab gene target failure (pOGTF) on the cobas ® SARS-CoV-2 assays, defined by a ≥2 thermocycles delay in detection of the ORF1ab gene compared to the E gene. We demonstrate that pOGTF is 97% sensitive and 99% specific for SARS-CoV-2 lineage BA.2.12.1, an emerging variant in the United States with spike L452Q and S704L mutations that may impact transmission, infectivity, and/or immune evasion. Increasing rates of pOGTF closely mirrored rates of BA.2.12.1 sequences uploaded to public databases, and, importantly increasing local rates of pOGTF also mirrored increasing overall test positivity. Use of pOGTF as a proxy for BA.2.12.1 provides faster tracking of the variant than whole-genome sequencing and can benefit laboratories without sequencing capabilities.
DOI10.1101/2022.04.25.22274187
Alternate JournalmedRxiv
PubMed ID35547854
PubMed Central IDPMC9094110
Grant ListL30 AI120149 / AI / NIAID NIH HHS / United States
Related Faculty:
Lars Westblade, Ph.D.
Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700 | {
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5,901,475,593,159,134,000 | Vol 27, No 2 (2023)
Original paper
Published online: 2023-03-13
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Variations in blood pressure in adolescents and its correlation with different anthropometric measurements: a cross-sectional study
Dev Himanshubhai Desai1, Aparajita Shukla1
Arterial Hypertension 2023;27(2):78-87.
Abstract
Background: Anthropometry is emerging as a useful tool in assessing the future risk of chronic diseases such as type 2 diabetes mellitus (and diabetic nephropathy, diabetic neuropathy, diabetic retinopathy), hypercholesterolemia, atherosclerosis, coronary artery diseases, nonalcoholic fatty liver disease (NAFLD). Body mass index (BMI) and waist–hip ratio (WHR) are used extensively in the forecast of cardio-vascular diseases. The main risk factor for such diseases is hypertension and the correlation of hypertension with BMI and/or WHR gives one the ability to forecast the diseases as risk assessment from a young age and proper techniques can be utilized to delay them. The aim of this study was to correlate BMI and WHR with hypertension in young adults and adolescents.
Material and methods: A cross sectional, record-based study of adolescents from age group 17–19 (n = 946) was done and analyzed.
Results: Data of a total of 465 males and 481 females (n = 946) were analyzed. In both males and females, mean blood pressure [both systolic (SBP) and diastolic blood pressure (DBP)] showed a positive correlation with increasing ranges of BMI and WHR. Values of Pearson correlation coefficient and p-value: Males: SBP -> BMI = 0.236 (p < 0.0001); DBP -> BMI = 0.187 (p < 0.0001); Males: SBP -> WHR = 0.194 (p < 0.0001); DBP -> WHR = 0.148 (p < 0.0001); Females: SBP -> BMI = 0.249 (p <0.0001); DBP -> BMI = 0.267 (p < 0.0001); Females: SBP -> WHR = 0.090 (p < 0.0001); DBP -> WHR= 0.116 (p < 0.0001). The correlation between BMI and WHR in males was 0.234 (p < 0.0001) and in females, it was 0.172 (p < 0.0001).
Conclusion: A steady increase in SBP and DBP is correlated with an increase in BMI and WHR. This leads to the efficacy of these methods in assessing future risks. It was found that hypertension was correlated with BMI and WHR; there was also a correlation between BMI and WHR.
Original paper
Variations in blood pressure in adolescents and its correlation with different anthropometric measurements: a cross-sectional study
Dev Himanshubhai DesaiAparajita Shukla
SMT. NHLMMC, VS-SVP Hospital, Ellisbridge, Ahmedabad, India
Address for correspondence: Dev Himanshubhai Desai, SMT. NHLMMC, VS-SVP Hospital, Ellisbridge, 380006 Ahmedabad, India; e-mail: devhdesai01@gmail.com
This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially
Abstract
Background: Anthropometry is emerging as a useful tool in assessing the future risk of chronic diseases such as type 2 diabetes mellitus (and diabetic nephropathy, diabetic neuropathy, diabetic retinopathy), hypercholesterolemia, atherosclerosis, coronary artery diseases, nonalcoholic fatty liver disease (NAFLD). Body mass index (BMI) and waist–hip ratio (WHR) are used extensively in the forecast of cardio-vascular diseases. The main risk factor for such diseases is hypertension and the correlation of hypertension with BMI and/or WHR gives one the ability to forecast the diseases as risk assessment from a young age and proper techniques can be utilized to delay them. The aim of this study was to correlate BMI and WHR with hypertension in young adults and adolescents.
Material and methods: A cross sectional, record-based study of adolescents from age group 17–19 (n = 946) was done and analyzed.
Results: Data of a total of 465 males and 481 females (n = 946) were analyzed. In both males and females, mean blood pressure [both systolic (SBP) and diastolic blood pressure (DBP)] showed a positive correlation with increasing ranges of BMI and WHR. Values of Pearson correlation coefficient and p-value: Males: SBP -> BMI = 0.236 (p < 0.0001); DBP -> BMI = 0.187 (p < 0.0001); Males: SBP -> WHR = 0.194 (p < 0.0001); DBP -> WHR = 0.148 (p < 0.0001); Females: SBP -> BMI = 0.249 (p <0.0001); DBP -> BMI = 0.267 (p < 0.0001); Females: SBP -> WHR = 0.090 (p < 0.0001); DBP -> WHR= 0.116 (p < 0.0001). The correlation between BMI and WHR in males was 0.234 (p < 0.0001) and in females, it was 0.172 (p < 0.0001).
Conclusion: A steady increase in SBP and DBP is correlated with an increase in BMI and WHR. This leads to the efficacy of these methods in assessing future risks. It was found that hypertension was correlated with BMI and WHR; there was also a correlation between BMI and WHR.
Key words: anthropometry; BMI; waist-hip ratio; hypertension; risks
Arterial Hypertens. 2023, vol. 27, no. 2, pages: 78–87
DOI: 10.5603/AH.a2023.0012
Introduction
Medical field in recent years has underwent serial new modifications and is evolving everyday catering to humans and battling diseases. Increase in life expectancy is one of the most important and the biggest achievement in the medical field. With increasing life expectancy, some chronic systemic diseases have shown a higher prevalence rate than before.
These chronic diseases namely coronary artery disease, atherosclerosis, myocardial infarction, hypertension, type 2 diabetes mellitus (and diabetic nephropathy, diabetic neuropathy, diabetic retinopathy), hypercholesterolemia, non-alcoholic fatty liver disease (NAFLD) are now prevalent in every country in every continent. Risk assessment of developing these has become the utmost priority in modern science. Assessing the chances of developing these diseases and working towards decreasing the modifiable factors is the key.
The prevalence of hypertension in young adults and adolescents is alarmingly increasing as per various news outlets. However, no specific study has confirmed this so far, although the prevalence of obesity and stress and other factors contributing to hypertension have significantly increased.
Anthropometry is currently emerging as one of the most useful tools to assess the risk of these diseases. Anthropometry refers to the use of height, weight, and hip and waist circumferences to derive specific value such as body mass index (BMI) or waist–hip ratio (WHR) to assess the health of any individual.
BMI and WHR are used extensively in forecasting cardio-vascular diseases. Waist circumference alone can also be used as an indicator of visceral fat. The main risk factor for the diseases mentioned above is hypertension [1]. The correlation of hypertension with BMI and/or WHR makes it possible to predict the risk of diseases from an early age and apply appropriate strategies to delay them.
More than half a century has passed since Gertler et al. reported in 1951 that young men at risk for coronary artery disease were about 5 cm shorter than their healthy counterparts [2, 3].
In males aged 15–19 years, there seem to be definite tendency for systolic blood pressure to increase with height. In the older age-groups there may be a slight tendency for systolic pressure to decrease with increasing height. Systolic blood pressure is always higher in the shortest height groups than in the tallest groups. This may be accidental, but the tendency is so systematic that it may reveal a biological fact. Since such a relationship is not observed in the middle age-groups, this is especially related to old age [4].
Shorter individuals have higher BP levels than taller individuals. This may at least partly explain the inverse association between height and cardiovascular disease (CVD) [5]. Short people may be more susceptible to the effects of ageing on the arterial tree. Childhood growth may contribute to tracking of cardiovascular risk throughout life [6].
In adults of Western societies, the positive relationship between blood pressure and body weight has often been demonstrated, both cross-sectionally and longitudinally. This correlation is even stronger in children and young adults [7].
Tracking of blood pressure: If blood pressure levels of an individual were followed up for over a period of years from early childhood into adult life, then those individuals whose pressure were initially high in the distribution, would probably continue in the same track as adults. In other words, low blood pressure levels tend to remain low, and high levels tend to become higher as individuals grow older [8, 9]. This means that if blood pressure is on the slightly higher side.
The main aim of the study was to see if height, weight, waist circumference, and hip circumferences have any impact on a person’s blood pressure. It can be stated with no doubt here that young population has a more vibrant cardiovascular system that can withstand the hypertensive stress and any other type of insults done on it. With increasing age, resilience and compliance along with elasticity of the cardiovascular system decreases. If, in young adolescents, it can be found that height and weight of individuals has a significant effect on blood pressure, it can be understood that with ageing, the impact of height and weight will only increase leading to higher changes in blood pressure and the relation between height and weight with blood pressure will only grow stronger. BMI and WHR are the main indices of height and weight measurement and are the impacting factors on blood pressure. We also wanted to see what is more reliable between BMI and WHR in assessing risk of chronic diseases and mainly hypertension.
Material and methods
Community Medicine Department affiliated with the Medical College every year collects data of new students admitted to the institute for research purposes of the department itself. The department here gathers wide range of data related to height, weight, waist and hip circumferences and blood pressure.
A cross-sectional study was designed to collect data. The records of last 4 years (records of the data collected by the department of the students who were admitted in the medical college in the last 4 years) obtained from Community Medicine Department were used in the study. At the time of data recording, the students signed informed consent form for the data they are providing. Yet, in the data acquisition for this research, identity of the subjects were not revealed.
All subjects belonged to the age group of 17–19 when the data was recorded at given point of time in last 4 years. This data from physical files was collected and digitalized so that proper statistical tests could be applied and results could be achieved.
As the data had been collected already and no interaction was done with the actual participants, the Ethical Board gave oral permission and no written permission was taken. The head of the Community Medicine Department gave her permission for the use of the said records for the purpose of this research.
Study design
Record-based cross-sectional study (records were collected originally by the Community Medicine Department).
Study population
Records of 946 students were included in the study, of them 481 were females and 465 were males.
Exclusion criteria were as follows:
• data was not recorded of any student having any predisposed or known medical conditions that are chronic in nature;
• who did not give consent at the time of data recording.
Measurements done on every subject
They all were made to sit in a classroom for 30 minutes for form filling to record all data that had to be gathered by the Community Medicine Department. The measurements were taken with the use of measure tapes which were put around the waist and hip for their circumference. A carefully calibrated weighing scale was used for the measurement of weight and for height, properly calibrated vertical instrument was used. The measurements included:
• height;
• weight;
• circumference at hips;
• circumference at waist
• blood pressure (both systolic and diastolic).
Derivations of measurements used in analysis
BMI [kg/m2] was defined as the body mass divided by the square of the body height, and is expressed in units of kg/m2, resulting from mass in kilograms and height in meters [10]. Formula:
mass [kg]/[height (in meters)2]
Normal values:
• < 18.5 underweight;
• 18.5–21.75 normal (lower range);
• 21.75–25 normal (upper range);
• 25–30 overweight;
• > 30 obese.
WHR was defined as the dimension less of the circumference of the waist to that of the hips [11].
Formula:
Circumference of waist/Circumference of hip
Normal values:
• < 0.75 underweight;
• 0.75–0.8 normal (lower range);
• 0.8–0.85 normal (upper range);
• 0.85–0.9 overweight;
• > 0.9 obese.
Blood pressure [mm Hg], systolic (SBP) and diastolic (DBP), was taken three times and all three values were denoted in the records. The authors entered all three values and calculated the mean of it to put for further statistical analysis and results.
Statistical analysis was done with Microsoft Excel and SPSS 20. Statistical tests conducted:
• average;
• standard deviation;
• comparative analysis across ranges;
• standard error of the mean (SEM);
• confidence interval (95% CI);
• Pearson correlation (r value);
• statistically significant test (unpaired t test) (p-value);
• analysis of variance (ANOVA) (f statistics);
• charts and tables.
Results
Gender distribution in the study population is presented in Table 1.
Table 1. Sex distribution in the study population
Females
Males
Total
Number of participants
481
465
946
All data from the participants were gathered when they entered the Medical College as first-year students and hence all were from 17–19 age group.
Preliminary results and analysis
Table 2 and Table 3 provide sufficient evidence that in both males and females the average levels of both SBP and diastolic DBP are increasing with increasing ranges of BMI. Pearson’s correlation test results [R value = 0.249 (BMI vs. SBP); R value = 0.267 (BMI vs. DBP)] (Fig. 1 and 2; Tab. 2) show that both SBP and DBP is positively correlated with BMI in female participants (p < 0.0001). In addition, the results of Pearson’s correlation test [R value = 0.236 (BMI vs. SBP); R values = 0.187 (BMI vs. DBP)] (Fig. 3 and 4; Tab. 3) demonstrate considerable increases in SBP and DBP with increasing ranges of BMI in male participants (p < 0.0001).
Table 2. Blood pressure (BP) in females in different body mass index (BMI) ranges
BMI
ANOVA F-statistics (p-value)
< 18.50
18.5021.75
21.7525.00
25.0030.00
> 30.00
SBP
Average
115.97
116.27
119.69
127.25
127.73
14.18 (< 0.0001)
SD
13.65
11.79
12.18
11.89
14.10
N
126.00
157.00
102.00
67.00
26.00
SEM
1.22
0.94
1.21
1.45
2.77
95% CI
2.38
1.84
2.36
2.85
5.42
DBP
Average
74.98
75.05
78.17
84.49
85.23
12.59 (< 0.0001)
SD
11.24
9.70
11.00
8.29
13.32
N
123.00
155.00
101.00
67.00
26.00
SEM
1.01
0.78
1.09
1.01
2.61
95% CI
1.99
1.53
2.15
1.99
5.12
p
< 0.0001
< 0.0001
< 0.0001
< 0.0001
< 0.0001
R value = 0.249 (BMI vs. SBP) Æ R values = 0.267 (BMI vs. DBP)
Table 3. Blood pressure (BP) in males in different body mass index (BMI) ranges
BMI
ANOVA F-statistics (p-value)
< 18.50
18.5021.75
21.7525.00
25.0030.00
> 30.00
SBP
Average
125.19
127.91
131.12
133.30
133.41
6.92 (< 0.0001)
Standard deviation
11.51
11.44
12.35
12.31
11.93
N
79.00
105.00
132.00
97.00
39.00
SEM
1.29
1.12
1.08
1.25
1.91
CI95
2.54
2.19
2.11
2.45
3.74
DBP
Average
77.41
80.50
82.43
83.14
83.53
5.32 (< 0.0001)
SD
11.83
10.69
7.70
8.79
6.97
N
75.00
105.00
129.00
94.00
36.00
SEM
1.37
1.04
0.68
0.91
1.16
95% CI
2.68
2.04
1.33
1.78
2.28
p
< 0.0001
< 0.0001
< 0.0001
< 0.0001
< 0.0001
R value = 0.236 (BMI vs. SBP) Æ R values = 0.187 (BMI vs. DBP)
53039.png
Figure 1. Confidence interval (CI) range and average in females. Systolic blood pressure (SBP) vs. body mass index (BMI)
53064.png
Figure 2. Confidence interval (CI) range and average in females. Diastolic blood pressure (DBP) vs. body mass index (BMI)
53068.png
Figure 3. Confidence interval (CI) range and average in males. Systolic blood pressure (SBP) vs. body mass index (BMI)
53075.png
Figure 4. Confidence interval (CI) range and average in males. Diastolic blood pressure (DBP) vs. body mass index (BMI)
Table 4 and Table 5 are sufficient to infer that in both males and females the average levels of both SBP and DBP are increasing with the increasing ranges of WHR. Pearson’s correlation test results [R value = 0.090 (WHR vs. SBP); R values = 0.1157 (WHR vs. DBP)], (Fig. 5 and 6; Tab. 4) show that both SBP and DBP are positively correlated with WHR in female participants (p < 0.0001). In addition, the results of Pearson’s correlation test [R value = 0.194 (WHR vs. SBP); R value = 0.148 (WHR vs. DBP)] (Fig. 7 and 8; Tab. 5) demonstrate considerable increases in SBP and DBP with increasing ranges of WHR in male participants (p < 0.0001).
Table 4. Blood pressure (BP) in females in different waist-to-hip ratio (WHR) ranges
WHR
ANOVA F-statistics (p-value)
< 0.75
0.750.80
0.800.85
0.850.90
> 0.90
SBP
Average
117.44
119.32
120.17
122.29
124.12
2.69 (0.031)
SD
11.47
14.20
12.55
12.40
12.64
N
95.00
135.00
133.00
66.00
42.00
SEM
1.18
1.22
1.09
1.53
1.95
95 % CI
2.31
2.40
2.13
2.99
3.82
DBP
Average
74.97
78.37
78.38
79.70
81.02
3.20 (0.013)
SD
10.55
12.16
9.09
10.16
10.66
N
93.00
134.00
133.00
64.00
41.00
SEM
1.09
1.05
0.79
1.27
1.66
95% CI
2.14
2.06
1.54
2.49
3.26
P
< 0.0001
< 0.0001
< 0.0001
< 0.0001
< 0.0001
R value = 0.090 (WHR vs. SBP) Æ R values = 0.187 (WHR vs. DBP)
Table 5. Blood pressure (BP) in males in different waist-to-hip ratio (WHR) ranges
WHR
ANOVA F stat
< 0.75
0.750.80
0.800.85
0.850.90
> 0.90
SBP
Average
122.50
125.66
128.60
131.53
132.85
5.67 (<0.0001)
SD
7.60
11.44
13.06
11.35
12.73
N
16.00
47.00
87.00
136.00
145.00
SEM
1.90
1.67
1.40
0.97
1.06
95% CI
3.72
3.27
2.74
1.91
2.07
DBP
Average
77.87
79.45
80.28
81.13
83.16
2.40 (0.049)
SD
7.69
8.08
10.81
11.01
8.44
N
15.00
47.00
83.00
134.00
141.00
SEM
1.99
1.18
1.19
0.95
0.71
95% CI
3.89
2.31
2.33
1.86
1.39
p
< 0.0001
< 0.0001
< 0.0001
< 0.0001
< 0.0001
R value = 0.194 (WHRvsSBP) Æ R values = 0.148 (WHRvsDBP)
53119.png
Figure 5. Confidence interval (CI) range and average in females. Systolic blood pressure (SBP) vs. waist-hip ratio (WHR)
53120.png
Figure 6. Confidence interval (CI) range and average in females. Diastolic blood pressure (DBP) vs.waist-hip ratio (WHR)
53126.png
Figure 7. Confidence interval (CI) range and average in males. Systolic blood pressure (SBP) vs. waist-hip ratio (WHR)
53131.png
Figure 8. Confidence interval (CI) range and average in males. Diastolic blood pressure (DBP) vs. waist-hip ratio (WHR)
Table 6 and Figure 9 show the relation between BMI and WHR in female patients, assessed using Pearson’s correlation coefficient (R value), and Table 7 and Figure 10 show the relation between BMI and WHO in male patients.
Table 6. Relation between body mass index (BMI) and waist-to-hip ratio (WHR) in female patients
BMI
WHR
BMI
1
WHR
0.17
1
Desai-09.jpg
Figure 9. Relation between body mass index (BMI) and waist-to-hip ratio (WHR) in female patients
Table 7. Relation between body mass index (BMI) and waist-to-hip ratio (WHR) in male patients
BMI
WHR
BMI
1
WHR
0.23
1
Desai-10.png
Figure 10. Relation between body mass index (BMI) and waist-to-hip ratio (WHR) in male patients
Table 6, Figure 9, Table 7 and Figure 10 show that in both males and females BMI is correlated with WHR and both show similarity in trends, as the Pearson’s correlation coefficient although weak is still positive.
Discussion
While formulating comparison with research papers which try to show relationship between blood pressure and BMI, it was found that the results are aligned with a similar study on older study sample in Chinese population (mean age was 55.7 ± 9.8) [12], on Italian population (mean age was 55.4 ± 15) [13], and in Ghana (age groups 30–50) [14]. All of these studies indicate a direct increase in both SBP and DBP with increasing BMI ranges.
In a comparative study conducted by WHO [15] between different ethnicities of developing country, it was seen that BP was positively correlated with age and BMI, but almost no correlation was found between BMI and age itself or it was negative. A comparative study conducted in Africa [16] on lean population (BMI range 20–28) from Nigeria, Cameroon, Zimbabwe and Jamaica, a nonlinear (instead of linear [15]) was found between BMI and BP, which is the same trend as seen in our study. Similar trends of BMI and BP relations are seen in studies conducted in South Asia (stronger correlation at low cut off points of overweight) [17] and in Delhi, India (age group 18–50 showing pre-hypertensive conditions are correlated with BMI) [18] and in North-East India (where odd ratios showed overweight/obese subjects to be more likely to have hypertension than those with normal BMI) [19].
A study conducted on urban population of India suggested that BP correlates with BMI, weight and WHR but not with age and height [20] in contrast to papers [12–14, 18] where age was a factor affecting BP. A South African study on young women both waist circumference and hip circumference were correlated with pre-hypertension and hypertension [21]. Another study suggested that WC and WHR are positive correlation with BP and hence concludes that abdominal obesity may be considered as an important risk factor of CVD. The study suggested that WC and WHR has positively correlated with BP and hence concludes that abdominal obesity may be considered as an important risk factor of CVD [22].
A research conducted at NTB general hospital in Indonesia [23] found that BMI was not correlated with BP (was not statistically significant; the results were mainly because study sample was smaller (61) and all patients were selected based on the criterion that they were already in the cardiology department due to hypertension), and another research found that in middle-aged men, a central distribution of body fat is associated with increased BP, independently of body mass index and insulin resistance [24].
A study published in International Journal of Contemporary Pediatrics, which is very close to our research design, showed that increased BMI and WC are good predictors of the increase in SBP and DBP. The authors suggested measurement of WC as a screening tool for childhood hypertension, because WC is easier to measure than blood pressure in terms of training and access to equipment [25]. Another similar study which was published in Nature News also came to a conclusion that BMI and WHR are strongly correlated with pre-hypertensive and hypertensive conditions and they found that BMI is superior than WHR in predicting elevated BP [26].
The above discussion suggests that weak correlation can be established between BMI and WHR, which means that both are interdependent. BMI and WHR are interdependent but the correlation coefficient is so weak that in clinical practice they can be taken as independent factors without any significant change in clinical outcome.
This also gives sufficient evidence to state that blood pressure increases with increasing BMI and WHR, even in healthy adolescents and young adults without any type of co-morbidity. Nowadays, it is generally seen that WHR is considered more important while assessing risk of chronic diseases as, arguably, BMI does not differentiate between fat weight, muscle weight and bone weight. However, looking at the trends of Pearson’s correlation coefficient (R value), the correlation of BMI with blood pressure (both SBP and DBP) is stronger than that of WHR. Although R value for both BMI and WHR is not that strong, R value for BMI is higher in both males and females than for WHR.
The point is that the cardiovascular system is young and the most compliant and fresh without any morbidity. It can be thought of as the healthiest it will ever be. Most elastic and resilient it will ever be, and yet, the variation in both SBP and DBP was significant. With progressive damage and wear and tear of cardiovascular system and end-organ damage at multisystem level, in elderly the whole situation would be seen amplified. If small changes with different BMI and WHR ranges are so evident at young age, these changes will be multiplied largely with small changes in BMI and WHR at older ages when cardiovascular system’s function will be diminished. This result and hypothesis can be taken into consideration as an interventional type of study to educate people in how maintenance of their health and body weight is important, as they can lead to disastrous outcomes with passing of time. If adolescent show this much changes of average ±10 mm Hg with the whole range of BMI and WHR, it would make a difference of hypotensive to hypertensive in elderly which can alter their whole lifestyle and survival rate. With diseases involving blood pressure, it is a matter of time that a patient would succumb to other chronic diseases namely coronary artery disease, type 2 diabetes mellitus, nephropathies, end-organ damage, vascular diseases, aneurysms, and other deadly conditions with lesser and lesser survival rate.
Conclusion
With increasing body weight or BMI or WHR, average blood pressure (both SBP and DBP) increases significantly even in young adults and adolescents. BMI and WHR show a weak but positive correlation with SBP and DBP and can be considered independent tools and separate entities when the need of using them in clinical practice arises. BMI has been found to be more reliable in assessing future risk of chronic disease than WHR.
Limitations
There are limitations of this study:
• small sample size: anthropometric researches usually require a very large sample size and even though we got statistically significant result, a larger sample size would mean a better estimation of actual average and hence a more accurate model;
• less randomization in sample: students whose data was actually used, although belonging to a wide range of population and representative of all strata, still the students belonged to the same country; additionally similar data of various countries could be taken here for a better applicability of the model
Further studies and interventions are suggested:
• a larger sample size can be taken for anthropometrical study like this;
• interventional study can be taken up with similar risk group and genetic disposition patient (future patients) and can be compared with a control group.
Longitudinal study on same study cohorts can yield better and more accurate findings for future predictions. (This study sample were medical students and, in their training, they will have mainly sedentary lifestyle resulting in weight gain. Another study can be organized here with main focus on the effects of primary prevention (life style changes) and its efficacy.)
Data availability
Availability of data and materials: the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request
Conflict of interests
The authors declare that they have no competing interests.
Funding
None declared.
Authors’ contributions
D.D. digitalized the data from the records and then analyzed it, made results and was major in writing the manuscript. A.S. was key in analysis of the data and writing of manuscript.
Ethical consideration
The research protocol was waived by relevant institutional review boards as it was a record-based study, and the authors have no conflict of interest to declare. The authors have not received any funding from anyone for this research project and have no financial dilemma.
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-6,425,621,871,047,399,000 | Tennis Elbow
Photo Credit: Kos Public Domain
Painful joints, tendons and muscles of the elbow may indicate a condition known as lateral epicondylitis or tennis elbow. As the name implies, tennis players who have not perfected the backhand return can suffer strained tendons that cause the pain of tennis elbow. Anyone may suffer this condition. Tennis elbow is caused by overworked tendons. People who engage in repetitive motions of the wrist and arm can be susceptible to tennis elbow. The pain may remain localized in the elbow or it can spread to the forearm and wrist. Severe tennis elbow pain can be debilitating. It can be difficult to turn a doorknob, pick up a coffee cup or hold a cooking pot by the handle. Tennis elbow will usually clear up on its own with some basic home-treatments. See a doctor if rest, ice and over-the-counter anti-inflammatory pain relievers do not relieve symptoms of tennis elbow.
Tennis elbow can affect anyone who engages in repetitive motion of the hand, wrist and arm, but some people are more susceptible to this painful condition. Chefs, painters, carpenters, plumbers and butchers often suffer from tennis elbow because of the daily repetition of the same arm movements. There are some ways to avoid this condition. First, learn the proper form when playing tennis, racquetball or golf. The swinging motion of the arm can result in stressed and injured tendons if the movement is not properly executed. When repetitive motions at work are the cause of tennis elbow, change to a more ergonomic way of performing the task. Raise or lower your chair if excessive use of a computer mouse is the culprit. Change the standard keyboard and computer mouse to ergonomically designed versions. Take frequent breaks from performing repetitive movements to stretch your arm muscles. Continue mild to moderate exercise as elbow pain allows and perform some stretching and strengthening exercises twice daily. Hold each exercise for up to 30 seconds and do up to 10 repetitions.
Sit on a sturdy chair, bend the affected elbow and place your forearm on your thigh. Hold a light, 1-pound dumbbell in your hand with your palm down, facing the floor. Your hand with the weight should be extended beyond your knee, far enough to allow the wrist and hand to move up and down without touching your knee. Slowly lift your wrist up toward the ceiling. Hold the position and then slowly lower your wrist down toward your knee and hold the position. After performing 10 repetitions, do the same exercise with your palm facing the ceiling while holding the dumbbell. Strengthen the tendons and muscles of your forearm by holding a dumbbell in your hand and extending your arm straight out in front of your body. Hold a dumbbell in your hand so that it is perpendicular to the floor. Your palm should be pointed toward your body. Rotate your hand and wrist until your palm is pointed at the floor. Slowly rotate back to the start position.
About Robin R.
I’m an AFPA certified personal trainer & nutrition consultant, NASM certified corrective exercise specialist, NASM certified youth exercise specialist, online fitness trainer and freelance writer specializing in health and fitness. I hold a Bachelor of Arts in psychology from the University of San Francisco and a Master of Science in natural health. I specialize in weight loss, functional strength training, total body toning, aerobic conditioning, plyometric training, nutrition planning, and home-based boot camp style workouts for women. My goal is to make every personal training session fun and effective for my clients. My services include online fitness training and professional content writing services at an affordable price for your business website or blog. I specialize in search engine optimization (SEO), article & blog writing.
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7,447,528,970,990,702,000 | The Most Common Toothbrushing Mistakes
The Most Common Toothbrushing Mistakes
Did you know that the way you brush your teeth can affect your oral health? While brushing your teeth is better than not brushing, making certain brushing mistakes can decrease how effective your daily brushings are. To help you improve your brushing routine, here are some of the most common tooth brushing mistakes you could be making:
large yellow toothbrush
Using a Hard Bristled Toothbrush
Toothbrushes that have stiff or hard bristles can be damaging to your teeth. For starters, they can weaken the enamel and cause dental erosion. They can also irritate your gums and cause gum recession. Therefore, the American Dental Association recommends using a brush with soft bristles that is long enough to reach the back of your mouth.
Using the Same Toothbrush
You should never use the same toothbrush for more than four months because it does not clean your teeth properly. In fact, it is recommended to replace your toothbrush every 3-4 months or sooner if you have been sick. You can tell it’s time to replac your toothbrush when the bristles become discolored, bent, or frayed.
Using Too Much Pressure
Contrary to popular belief, scrubbing your teeth does not make them cleaner. It can, however, contribute to enamel erosion and gum recession. Massaging the surface of your teeth with your toothbrush is enough pressure to remove plaque without damaging your teeth or gums.
Going Back and Forth
Just like scrubbing your teeth does not make them cleaner, moving your toothbrush back and forth also does not make your teeth cleaner. In fact, it can be just as damaging as applying too much pressure. The correct way to brush your teeth is to start at the gum line and move your toothbrush up and down in a circular motion.
diagram showing how to properly brush your teeth
Rushing
In order to adequately remove plaque and clean your teeth, you need to brush your teeth for two minutes twice a day. Trying to save time by skipping a brushing session or rushing through a brushing session can mean that plaque gets left behind on your teeth. This can eventually cause a cavity to develop.
Another mistake you may be making is that you are rushing to brush your teeth after meals. It is recommended to wait about 15-20 minutes after eating to allow your saliva to neutralize the acids from the food. Brushing too soon after a meal can cause damage to your enamel due to the high acid concentration.
Skipping Key Areas
One problem associated with rushing while brushing is that you tend to skip certain areas. In fact, there are two key areas that people often skip when brushing their teeth: along the gum line and the inside of their teeth. The gum line is especially important to brush because this is a common location for plaque buildup. Using your brush at a 45° angle is the best way to remove plaque along the gum line. Additionally, you will want to repeat this process on the inside of your teeth.
Rinsing
After you have finished brushing your teeth, you will want to spit out the excess toothpaste. However, you should not rinse your mouth with water. This is because toothpaste contains fluoride and you will want as much fluoride to remain on your teeth as possible. Fluoride is highly beneficial to your oral health because it strengthens your tooth enamel and prevents cavities.
Dr. Sam Sadati wearing black suite portrait
Dr. Sadati possesses extensive experience in all aspects of advanced restorative dentistry, with an emphasis in cosmetic and implant dentistry. He has attained Accredited Fellow status in the American Academy of Cosmetic Dentistry (AACD), the most rigorous, demanding credentialing process in the world. He is the only AACD Accredited Fellow in South Florida.
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6,251,933,675,731,194,000 | PMCCPMCCPMCC
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Logo of aidMary Ann Liebert, Inc.Mary Ann Liebert, Inc.JournalsSearchAlerts
AIDS Research and Human Retroviruses
AIDS Res Hum Retroviruses. 2011 September; 27(9): 1013–1017.
PMCID: PMC3161105
The Role of Dynamin in HIV Type 1 Env-Mediated Cell–Cell Fusion
Abstract
HIV-1 envelope glycoproteins are the key viral proteins that mediate HIV-1 entry and cell–cell fusion. In contrast to HIV-1 entry, the mechanism of HIV-1 Env-mediated cell–cell fusion is relatively unclear. This study demonstrated that dynasore, a dynamin inhibitor, suppressed HIV-1 Env-mediated cell–cell fusion. Dynasore sensitivity of HIV-1 Env-mediated cell–cell fusion varied depending on the viral strains. Results from testing a panel of gp41 cytoplasmic tail truncation mutants suggested that the gp41 cytoplasmic tail might play a role in dynasore sensitivity. HIV-1 Env-mediated cell–cell fusion could also be suppressed by a dynamin dominant-negative mutant DNM2(K44A). In summary, these results suggested that dynamin 2 might play a role in HIV-1 Env-mediated cell–cell fusion.
HIV-1 infection can result in fusion between susceptible CD4+ cells to form multinucleated syncytia. Similar to HIV-1 infection, syncytia formation involves the interaction between HIV-1 envelope glycoproteins and cellular receptor CD4 and chemokine receptors. It has been proposed that cell–cell fusion is a pathogenic mechanism that leads to CD4+ T cell depletion.13 In addition to its potential role in CD4 depletion, syncytia formation has also been implicated as an efficient mechanism of HIV-1 spread between infected and uninfected susceptible cells,4,5 although formation of virological synapses, nanotubes, and filopodial bridges might also mediate HIV-1 cell–cell spread.69
It is clear that HIV-1 gp120 and gp41 are the viral proteins that mediate both HIV-1 infection and HIV-1 Env-mediated cell–cell fusion. However, other than CD4 and chemokine receptors, cellular factors involved in the HIV-1 entry and HIV-1 Env-mediated cell–cell fusion remain to be further studied. The cellular protein dynamin 2 was implicated in HIV-1 entry through endocytosis.10 Dynamin 2 is a large cellular GTPase involved in the formation of endocytic vesicles through fission.11,12 It is interesting that dynamin could also mediate a seemingly reverse activity by being involved in membrane fusion.13,14 Although dynamin 2 was implicated in cell-free HIV-1 infection through endocytosis,10 it is not clear whether dynamin 2 might be involved in HIV-1 Env-mediated cell–cell fusion. Here, we used a cell–cell fusion model to show that dynamin 2 might play a role in HIV-1 Env-mediated cell–cell fusion.
To determine whether dynamin plays a role in HIV-1 Env-mediated cell–cell fusion, COS cells expressing HIV-1 Env from various HIV-1 strains were used to fuse with TZM-bl cells, a reporter cell line that expresses luciferase upon fusion15,16 in the presence of the dynamin GTPase inhibitor dynasore (Tocris Bioscience, Ellisville, MO). The HIV-1 sequence spanning env and tat genes were cloned into the expression vector pSHRS. The viral Envs used in this study were derived from the R5 viruses ADA, AC10.0.29, and YU-2; the X4 viruses NL4-3, HIV-1 8x, and Wtt; and the dual tropic virus DH012. ADA, NL4-3, and YU-2 were obtained from the NIH AIDS Research and Reference Reagent Program. AC10.0.29 (AC10) is a molecular clone derived from an R5 primary isolate.17 The DH012 Env used in this study contains gp120 from the dual tropic DH012 and gp41 from NL4-3.18 HIV-1 8x is an HIV-1 IIIB variant lacking the cytoplasmic tail of HIV-1 gp41, whereas Wtt is an HIV-1 8x revertant with the full gp41 cytoplasmic tail restored.1921 Electroporation was used to transfect COS cells with the expression vector pSRHS containing HIV-1 Env genes.16 COS cells (1×106 cells/ml) were transfected with HIV-1 Env-expressing vectors (0.5 μg) for 1 day before mixing with TZM-bl cells for fusion.
The sensitivities of the Env-mediated cell–cell fusions to dynasore varied among the tested HIV-1 Envs in the order of DH012>NL4-3=Wtt>YU-2>AC10.0.29>8x>ADA (Fig. 1a). The dynasore concentration required to inhibit DH012-Env mediated cell–cell fusion by 50% (IC50) is 34 μM, whereas the IC50 for HIV-1 ADA Env-mediated cell–cell fusion is >230 μM. As shown in Fig. 1b, the effect of dynasore on HIV-1 Env-mediated cell–cell fusion was not due to cytotoxicity. Under the experimental conditions, dynasore had minimal cytotoxicity against both COS and TZM-bl cells at 230 μM. The differential sensitivity of various HIV-1 Envs to dynasore suggested that dynamin played a role in HIV-1 envelope-mediated cell–cell fusion. The differential dynasore sensitivity also supported the notion that inhibition of the HIV-1 Env-mediated cell–cell fusion was not due to cytotoxicity.
FIG. 1.
Inhibition of HIV-1 Env-mediated cell–cell fusion by dynasore. (a) HIV-1 Env expressing COS cells were fused with TZM-bl cells for 24 h. Fusion of each Env in the presence of dynasore is defined as percent of fusion with dynasore/fusion ...
The IC50 of dynasore against Wtt-Env-mediated cell–cell fusion was approximately 57 μM, whereas the IC50 for the 8x-Env was greater than 230 μM (Fig. 1a). This differential sensitivity of Wtt and 8x to dynasore was not due to differential surface expression or the fusion efficiency of the Envs (Fig. 1b). The two Envs had similar fusion efficiency in the presence of low concentrations of dynasore. FACS analysis also indicated that the two envelopes had a similar level of surface expression (Fig. 1b, inset). The only difference between the two viruses is that 8x lacks the cytoplasmic tail of gp41. The differential sensitivities between Wtt and 8x to dynasore suggested that the cytoplasmic tail of HIV-1 gp41 might be a key determinant for the dynasore inhibitory activity. HIV-1 gp41 contains a long cytoplasmic tail (CT) of approximately 150 amino acids. The CT is highly conserved in length and sequence across diverse strains of HIV-1, suggesting functional significance for this region of the HIV Env. The CT contains an antibody-reactive putative beta turn region22,23 and three conserved alpha helical domains. The conserved alpha helical domains are also termed lentivirus lytic peptides (LLP).24,25
To determine the gp41 cytoplasmic motifs that are critical for dynasore sensitivity, a series of Wtt gp41 cytoplasmic tail truncation mutants were used in the Env-mediated cell–cell fusion assay (Table 1a). Wtt-Env mutants, Wtt.802, Wtt.769, and Wtt.723, remained quite sensitive to dynasore when most of the cytoplasmic tail was truncated from the C-terminus (Table 1b). In contrast, Wtt.707, Wtt.714, and Wtt.718, completely lacking or with a short cytoplasmic tail (0–12 amino acids), were much less sensitive to dynasore (Table 1b). It is interesting that Wtt.723 was at least 5-fold more sensitive to dynasore when compared to Wtt.718, even though the Env surface expression level of Wtt.723 and Wtt.718 was comparable (data not shown). Substitution of amino acids 719–723 of Wtt.723 with five alanines resulted in a construct, Wtt.7235A, that was much less sensitive to dynasore. In contrast to dynasore, the HIV-1 entry inhibitor IC9564 was equally potent against Wtt.723 and Wtt.718. IC9564 is a betulinic acid derivative that targets HIV-1 gp120.26 This result further supported the notion that there was a differential interaction between dynamin and the two HIV-1 Env variants, which might be responsible for their differential sensitivity to dynasore.
Table 1.
Differential Sensitivity of HIV-1 Wtt Variants to Dynasore
Endocytosis was implicated as a route for HIV-1 infection.10,2730 An endocytic motif YXXØ (amino acid residues 712–715) resides in the N-terminus of the gp41 cytoplasmic tail.3133 To determine whether the YXXØ motif affects dynasore sensitivity of HIV-1 Env-mediated cell–cell fusion, the YXXØ motif of Wtt.718 was mutated to GXXØ in Wtt .718(Y712G). The data in Table 1b show that knocking out the endocytic motif did not affect dynasore sensitivity.
To further determine the role of dynamin 2 in HIV-1 Env-mediated cell–cell fusion, a dominant negative dynamin 2 mutant, DNM2(K44A), was tested for its effect on HIV-1 Env-mediated cell–cell fusion. AC10.0.29, YU2, 8x, ADA, or DH012 Env expression vectors were cotransfected into COS cells with either wild-type dynamin 2, the dominant negative DNM2(K44A) mutant, or an empty expression vector as a control. Env expressing COS cells were mixed with TZM-bl cells and Env-mediated cell–cell fusion was measured at various time points. The dominant negative mutant DNM2(K44A) inhibited YU-2 and AC10 Env-mediated cell–cell fusions by more than 75%, 9 h after initiation of cell–cell fusion (Fig. 2). The inhibitory effect was not as strong at 24 h but fusion was still inhibited at this time point by approximately 50%. Similar to the lack of sensitivity to dynasore, ADA, and 8x Env-mediated cell–cell fusion were also resistant to DNM2(K44A). On the other hand, DH012 Env-mediated cell–cell fusion was very sensitive to dynasore inhibition when compared to YU-2 and AC10 (Fig. 1a). However, DH012 Env-mediated cell–cell fusions did not exhibit such a differential sensitivity to DNM2(K44A). The lack of correlation between dynasore and DNM2(K44A) sensitivity suggested that the mechanism of inhibition by the two dynamin inhibitors might not be the same.
FIG. 2.
Inhibition of HIV-1 Env-mediated cell–cell fusion by dynamin dominant negative mutant DNM2(K44A). Plasmids expressing dynamin 2 and a mutant, DNM2 and DNM2(K44A), were kindly provided by Drs. Pizzato and Göttlinger.38 DNM2, DNM2(K44A), ...
Dynamin 2 was implicated in HIV-1 virus entry by regulating the fusion between virus and endosome.10 Results from this study showed that Env from various HIV-1 strains including R5, X4, and dual-tropic viruses exhibited a range of sensitivity to dynasore. The fact that a greater than 5-fold difference in dynasore sensitivity between Wtt.723 and Wtt.718 suggests that the cytoplasmic tail of gp41 might be an important determinant for dynasore sensitivity.
Dynamin was linked to vacuole fusion mediated by SNARE. The SNARE proteins mediate membrane fusion through conformational changes and formation of helix bundles.34,35 This is reminiscent of HIV-1 gp41-mediated membrane fusion that involves both conformational changes and formation of 6-helix bundles. It is possible that there might be a direct or indirect interaction between dynamin 2 and gp41. However, it is not clear why some HIV-1 Env-mediated cell–cell fusion, such as that of ADA and 8x, are not sensitive to dynasore. One possible explanation for the lack of dynasore sensitivity is that these HIV-1 Envs might be able to mediate cell–cell fusion without dynamin. It is well documented that HIV-1 might enter susceptible cells through different mechanisms including transcytosis, endocytosis, and fusion of virus and cell membrane.36 Dynamin 2 was implicated in free HIV-1 entry through endocytosis. On the other hand, it is not clear whether dynamin 2 plays a role in the fusion of virus and cell membrane. Many viral and cellular factors, such as variation in Env sequence, level of receptor expression, or cell type, may affect the Env-mediated cell–cell fusion. Thus, it is possible that dynamin 2 is not required for ADA and 8x Env-mediated cell–cell fusion. In summary, the results of this study suggested that dynamin 2 might play a role in HIV-1 Env-mediated cell–cell fusion.37,38 By regulating HIV-1 Env-mediated cell–cell fusion, dynamin 2 might play a role in viral spread from infected cells to uninfected cells and HIV-1 pathogenesis.
Acknowledgments
This study was supported by the Collaboration for AIDS Vaccine Discovery (Bill and Melinda Gates Foundation) and by the U.S. National Institutes of Health (AI065310).
Author Disclosure Statement
No competing financial interests exist.
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Articles from AIDS Research and Human Retroviruses are provided here courtesy of Mary Ann Liebert, Inc.
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Chromium is the main additive in stainless steel, to which it adds anti-corrosive properties.Chromium is also highly valued as a metal that is able to be highly ⦠Chromium Chromium is an open-source browser project that aims to build a safer, faster, and more stable way for all users to experience the web. The information provided here is not sufficient for interface builds; for a complete test mix, please click the sidebar link to access the Interface Map. Previously, cobalt salts ⦠It is the first element in group 6.It is a steely-grey, lustrous, hard and brittle transition metal. View Details. We have made over 300 laboratory tests available direct to you, with everything from individual markers like vitamins and hormones, to fully ⦠LabCorp's test menu provides a comprehensive list of specialty and general laboratory testing services. Why is Blood Testing Critical? Principle An air sample is collected on a 37-mm polyvinyl chloride (PVC) filter [Note: Cellulose ester filters are unacceptable because they may react with and reduce the hexavalent chromium [Cr(VI)] ⦠Blood ⦠If youâve been taking chromium and youâre convinced that itâs helped your diabetes control (apart from medication, healthy eating, physical activity, weight loss, and potentially any other ⦠Serum Cholinesterase test is a test conducted to determine the levels of acetylcholinesterase and pseudocholinesterase in the blood. Chromium, Blood Test This blood test is used to determine chromium levels for deficiency or toxicity. Blood cobalt levels can be used in the assessment of occupational exposure or toxic ingestion. This site contains design documents, architecture overviews, testing information, and more to help you learn to build and work with the Chromium source code. Chromium is a chemical element with the symbol Cr and atomic number 24. Hexavalent chromium is also reported to have had harmful effects on human body. Chromium toxicity, which typically occurs due to workplace exposure, can be dangerous to a person's health.The most common form of exposure to Chromium is inhalation.Chromium ⦠A brief overview of the assay principle is ⦠These two substances are responsible to help the nervous system work efficiently. They are also referred as neurotransmitters. Here, I will outline a simple method for testing T ⦠It is important to have your blood drawn and shipped on the same day. A blood allergy test can be advantageous compared to a skin test because it can be done at any time, regardless of any current medications you may be taking. There is a $25 fee to cover the kit costs ⦠Chromium(IV) has toxic and carcinogenic properties, whereas high levels of chromium(III) could even lead to damaging of the DNA. Another 10cc of blood was drawn and the chromium 51 level was measured. Below is a full list of all our private blood tests and blood test costs. Existing evidence does not allow the conclusion that exchange transfusion generally should be employed, however [Geller 2001]. This test is not recommended for martensitic 400 series stainless steels or for ferritic 400 series stainless steels with less than 16 % chromium because these steels will typically give a positive indication irrespective of the presence or absence of anodic surface contaminants (a âfalse failureâ). Testing Specimens may include Urine, Oral Fluid, Blood, Hair and Nails. of blood and labeling the red blood cells with chromium 51. The U.S. tops the list of the number of people suffering from chromium deficiency. Being exposed to excessive levels of chromium can lead to serious medical complications. Certain heavy metals are essential to good health, such as selenium and magnesium. Your doctor will be able to advise you of the most approprate test for your particular situation. Leading orthopedic surgeons recommend cobalt and chromium blood testing every three months for as long as a patient has a metal on metal hip in their bodies. Symptoms associated with cobalt toxicity vary based on route of exposure and may include cardiomyopathy, allergic dermatitis, pulmonary fibrosis, cough and ⦠Blood tests: Cobalt and chromium levels at regular intervals (at least annually, and approximately every three months thereafter where metal ion levels continue to increase) Consider revision if there are persistent symptoms, particularly where there are cross-sectional imaging abnormalities and/or where the levels of cobalt or chromium in the blood ⦠Since chromium may affect blood sugar levels, it is crucial that anyone taking diabetes medications, like insulin, only use chromium under the ⦠It may be effective at improving the bodyâs response to insulin or lowering blood sugar in those with diabetes. From this it's possible to work out the amount of blood in the body. 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2,877,716,300,059,646,500 | The human condition of pain is a part of life, but no one likes to suffer it unnecessarily. Finding the right medication to manage pain is an important aspect of healthcare. It can improve a patient’s quality of living. Tramadol is a cost-effective and reliable option among the many painkillers on the market. This comprehensive article will explore Tramadol’s effectiveness, affordability and benefits to those who are in pain.
Tramadol: What is it?
Tramadol is also known as Ultram and other brand names. It is a synthetic analgesic. It works by changing the way that the brain perceives the pain signals. Tramadol, unlike some other opioids is thought to have a low potential for addiction and misuse, making it the preferred choice of healthcare providers and patients.
Tramadol: How Does It Work?
Tramadol has a two-fold mechanism of action. It binds first to mu-opioid brain receptors, which are similar to those of drugs such as morphine and codeine. This helps to reduce the pain perception. Tramadol inhibits serotonin reuptake and norepinephrine reuptake, which are two neurotransmitters that are closely related to mood and emotional wellbeing. This dual mechanism can not only provide pain relief, but also improve the patient’s sense of overall well-being. Tramadol can brighten the outlook for those who are suffering from discomfort.
Affordable Pain Management: A Game-Changer
Tramadol’s affordability is one of its most notable features. Tramadol can be purchased at lower prices than other painkillers prescribed by doctors, making it more affordable for many patients. This affordability factor can be crucial for those without comprehensive insurance or on a limited budget.
Additional Savings with Generic Options
Generic versions of Tramadol are available at a lower price than the brand name. The FDA regulates these generic alternatives to ensure that they meet the same safety and quality standards as the brand-name equivalents. Generic options can save you money without compromising efficacy. For those who are looking for a way to manage their pain without going broke, this affordability is a great option.
Effectiveness and Versatility
Tramadol is effective in treating a wide range of pain conditions. It is prescribed to treat moderate-to-moderately severe pain that can be caused by a number of factors, such as injuries, surgery, chronic conditions and more. The versatility of this drug in treating different types of chronic pain makes it an important tool in pain management.
Reduce the risk of dependency
Tramadol, while an opioid, is different from other opioids in that it has a lower risk of addiction and dependence. The ‘weak opioid’ classification of Tramadol and its dual mechanism of action are responsible for its unique profile. Tramadol must be taken under the supervision of a medical professional and in accordance with prescribed dosages. The use of Tramadol responsibly minimizes potential risks, and helps to ensure that the medication is an effective tool for fighting pain.
Pain Management
Tramadol is a powerful pain reliever that has many other benefits. Tramadol allows patients to participate more actively in daily activities by reducing discomfort. This improves their quality of life. Effective pain management is important in healthcare because it can restore comfort and function. Effective pain management allows individuals to regain their independence, and enjoy the activities that they love. This strengthens their connection with their environment.
A Beacon of Relief
Tramadol is a painkiller that stands out for its affordability, effectiveness and versatility. Tramadol is a unique medication that offers pain relief for people who are looking for it. It’s important to consult a medical professional before taking any medication to determine the most effective treatment.
Tramadol is a great way to relieve pain for anyone who has been struggling with the challenges of managing their pain. Its effectiveness and accessibility make it an essential tool for achieving better health. Tramadol makes the prospect of living a pain-free life a reality.
Credits: https://usmedspharma.org/catalogue/pain-relief/tramadol/ & https://fifthplanet.net/tramadol-ultram/ | {
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-2,938,228,189,855,952,000 | Download family therapy emma bugg sexual health and wellness
Family therapy is a dynamic and evolving field that plays a crucial role in promoting overall well-being and mental health within familial relationships. This article delves into the multifaceted world of family therapy, exploring the principles, techniques, and benefits that underpin this therapeutic approach. Additionally, we will examine the influential contributions of Emma Bugg in … Continue reading Download family therapy emma bugg sexual health and wellness | {
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-5,406,825,557,072,643,000 | Tackling Tennis Elbow
Tackling Tennis Elbow
Published: 2021-03-11
Tennis elbow or lateral epicondylitis can be aggravating and chronic, here are a few remedies that I have used over the years.
First let's touch on what is going on where the tendon attaches on the lateral or outside on the epicondyle, the little boney prominence on the outside of the elbow joint. We have micro-tearing or tendinitis, which is inflammation of the attachment of the wrist extensors.
This can occur from strenuous overuse or from one acute blow and strain of the extensors. More often it occurs over time from repeated activity with a lever or racket going into pronation causing inflammation of the tendon.
If left untreated this could become a chronic or prolonged injury with loss of motion and function. It can be painful and aggravating. The biggest negative is it can easily become reoccurring.
Now let's discuss treatment options and rehab of this condition.
1. REST - back off what caused it, until the area quiets down and has no pain or discomfort. Stopping swinging the racket or hammer repeatedly.
2. Wear a tennis elbow brace for most of the day and night, snug but not too tight. This is a velcro strap, by Riptgear, or one can roll up a piece of underwrap to create a tether placed just below or distal to the epicondyle. This tends to shorten the tendon and in turn take stress off the attachment.
3. Take over -the- counter NSAID {non steroidal anti-inflammatory meds } such as Advil or Aleve. These must be taken properly with food and on time or be compliant with the proper dosage for 5-7 days. If these do not alleviate the pain or discomfort, visit a physician to have them prescribe a prescription medication or a properly placed cortisone injection. CBD oil or a diclofenac gel medication may also relieve some of the pain.
4. The last option and only if symptoms persist for a very long period of time, would be surgery.
In my opinion, I think this condition occurs due to extensor and pronator weakness from a repetitive action or on one single blow where a strain occurs on a max effort mishit; this inturn tears the tendon and gets things started. If the athlete or person has good grip strength as well as pronator and extensor strength there is less chance of injury.
So how do we strengthen these muscles?
Exercises to isolate and give the extensors and pronators endurance strength:
• Gripping putty, closing the hand fully into a fist with a gripping action, secondly using a hand gripper that lightly spring loaded to squeeze while driving or watching TV.
• Using a 1lb hammer or weight and performing pronation {palm down} and supination {palm up} exercises independently. DO NOT perform both motions at the same time or momentum will take over and you will not get the full benefit from these two exercises.
• Using a 1 lb hammer, a bat or tennis racket to do ulnar deviation which is the opposite of the hammer motion. Place the device out the back of the hand and reverse the hammering motion.
• Wrist rolling action with a stick and weight or a Power-stick device.
• Strengthen the extensor and flexor muscles of the wrist and forearm for the long haul, with a Marcy wrist device, which you can also work in ulnar deviation
The key is building endurance type strength in the motions listed above, but don't over do it. Do 3 sets of 10 repetitions on the exercises listed. One can also utilize tubing attached to a stick for eccentric type work once you are further along and pain free.
Treatment with the following modalities may also relieve the pain and discomfort. These are a cold point laser, ultrasound, contrast baths {alternating hot and cold}, ice after activity and exercises may also help.
When playing or exercising, grip the racket firmly. Work within a pain free range when exercising. Also work on shoulder strength to take the stress off of the elbow joint. | {
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-2,444,521,173,412,747,000 | ماساژ قلبی
29اردیبهشت
دستگاه ماساژ قلبی که مردهای را زنده کرد!
مردی که برای ۴۰ دقیقه از لحاظ پزشکی مرده اعلام شده بود، با استفاده از یک دستگاه انقلابی که عملیات نجاتبخش ماساژ قفسه سینه را انجام میدهد، به زندگی بازگشت.
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مبتلایان
فوتیها
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مبتلایان امروز
فوتیهای امروز
موارد بحرانی
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2,346,632,765,285,700,000 | How Long Does Pre-Workout Last?
Updated on February 26, 2023
William Toro
Published By: William Toro
Fact Checked by: Bridget MacDonald, RDN
Our Methodology
We personally test every products with our researchers, trainers and members. All products are ordered anonymously. We evaluate on point based system to determine ranking under each category. Learn More
Pre-workout supplements are a great way to help you be at your best. These supplements can increase your energy level and give you a little boost before a workout.
This article is going to talk about how long does pre-workout supplement lasts after taking it. Many factors determine how long the supplement will last, such as the type of workout, your weight, and what else you’ve been doing that day.
What Are the Pre-workout Supplements?
The pre-workouts are designed to make both your body and brain function at an optimal level, which means they are capable of enhancing the way you train. The main goal is to boost your workout performance.
They are designed to provide your body with all the nutrients it needs to function properly by providing you with extra oxygen and energy.
The stimulants in them are typically added for this purpose, but other ingredients like creatine may also be added to help support muscle growth. They may also contain other important nutrients like essential amino acids, for muscle recovery.
How Long Pre-Workout Stay In Your System?
After taking a pre-workout supplement, the effects of the pre workout last anywhere from 30 minutes to 2 hours on average. Which is more than sufficient for your gym session.
However, the time frame depends on which product you take. Every pre-workout supplement will have a different time frame. Some pre workout last longer up to 2 hours on an average where as few may not last more than 30 minutes.
For instance, for a pre-workout supplement to provide 30 minutes of benefit, it should generally contain caffeine which has a half-life of 6 hours in the body. That means that after 6 hours, 50% of the caffeine is still in your system and provides you with some energy boost that lasts about 45 minutes before being eliminated from your body. [1]
The other 50% of the caffeine has been metabolized by your liver and kidneys over the previous six hours and eliminated from the body via urine or sweat, also providing some benefits in terms of preventing dehydration during workouts when working out in hot or humid environments. The pre workout caffeine quantity also determines your daily caffeine intake.
Another pre-workouts to provide 30 minutes of benefit could contain Arginine. It has a half-life of approximately about 30-120 minutes, meaning that the benefits are present for about 1.5 hours before it is eliminated from the body. [2]
What Factors Can Influence How Long Your Pre Workout Supplement Lasts?
Many factors can influence how long does pre-workout lasts. Some of them are listed below:
Dosage
The dosage is one of the most critical factors to consider. If you take an optimum dose, then it will work as intended and you will experience positive effects such as increased energy levels and enhanced focus. However, if you take a small amount of the product, it may not be as effective. The same theory applies if you take a large dosage; you will feel tired shortly after taking the supplement and the effects may not last as long as expected.
How Often You Exercise
Depending on how frequently you exercise, your pre-exercise supplement can have different effects on your body chemistry all depending on what works for others.
Your Overall Health
If your overall health is poor, then it can negatively affect how long your pre-workout lasts. The more healthy your body is the better effects the product will have on you from taking it.
Other Supplements
Other supplements you are taking can also increase the quantity of fat that is stored in your body and affect how long your pre-workouts will last.
Your Weight
Your weight is the single most important factor in determining how long your pre-workout supplement will last. If you’re a lightweight individual, it’s going to take a lot shorter for your pre-workout supplement to fully absorb into your body before peak performance. Conversely, if you’re a very heavy person, your pre-workout supplement may not be fully absorbed before peak performance.
How to Know Is Pre-Workout Working?
How do you know whether a pre-workout supplement is working for you? If you notice that your energy level is higher than it normally is, or your focus is better than usual during your training session, then your supplement may be working as intended.
!
Does Pre Workout Has Any Side Effects?
No, generally pre workout doesn't has any side effect. But however, if you are experiencing negative side effects when using pre-workouts such as nausea, headaches, or mental fogging which are making your workout session difficult to complete, then the pre-workout may not be for you. Try taking a few days off from taking the product to assess if it does work for your body and constitution. Always start pre workout in smaller quantities.
One of the side effect few notice is that some ingredients like beta alanine in pre workout supplement may cause tingling sensation in the first 30 minutes for some people, but its not alarming. Beta alanine is an amino acid which helps in increasing muscle endurance and delay muscle fatigue.
!
Caffeine in pre workout and its lasting effect?
As discussed earlier when taking pre workout you also consume caffeine. Which can range any where from 40mg to 400mg at a time.
As per Food and Drug Administration, caffeine consumption up to 400mg a day , isn't associated with any negative side effects. Though individual tolerance may vary. (3)
If you have low tolerance to caffeine, we suggest you to go with pre-workouts without caffeine to start with.
The duration of a single pre-workout dose will depend on the product you are using because each one has its effectiveness and serving size.
You can also check on benefits of pre workout here.
Summary
This conclusion will give you the information you need about how long does pre-workout lasts. There is a lot of variation between people and not everyone will experience the same effects. However, a single supplement can have a different effect on each person associated with it.
The most important thing to take from this article is that pre-workout supplements from most pre-workout supplements brands last from 30 to 60 minutes. They are effective for people who exercise regularly and have healthy lifestyles.
William Toro
William Toro ‧ CPT & Nutritionist
William is a certified personal trainer from NASM, he has also been a rehab physiologist for sports persons. He has more than 15 years of experience training people. And has featured in multiple publications like FoxNews, CNBC, Bustle, and other.
References:
1. Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations, Pharmacology of Caffeine, retrieved from https://www.ncbi.nlm.nih.gov/books/NBK223808/
2. Aitor Viribay, José Burgos, Julen Fernández-Landa, Jesús Seco-Calvo, Juan Mielgo-Ayuso, Effects of Arginine Supplementation on Athletic Performance Based on Energy Metabolism: A Systematic Review and Meta-Analysis, retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282262/
3. https://www.fda.gov/consumers/consumer-updates/spilling-beans-how-much-caffeine-too-much#:~:text=For%20healthy%20adults%2C%20the%20FDA,associated%20with%20dangerous%2C%20negative%20effects.
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4,618,961,791,450,300,000 | Stay Update with Global New Things
Exactly what Common Symptoms of Adult ATTENTION DEFICIT-HYPERACTIVITY DISORDER
11
What are common symptoms of grownup ADHD, and how do these kinds differ from symptoms in youngsters? ADHD is a disorder additionally discovered in childhood. To meet rapport criteria, according to the DSM- IV-TR (Diagnostic and Data Manual version IV- Written text Revision), symptoms of the ailment must be present by growing older 7.
Even though symptoms or perhaps mild forms of the ailment may be present in childhood, it is not necessarily uncommon for it to be uncovered or seek treatment for doing this only in adulthood. At the moment, there is not a separate symptom set of guidelines for the diagnosis of ADHD in older adults. Criteria for ADHD inside childhood are often used and also adapted to better account for the main living and developmental levels of adults.
Symptoms throughout children and adults largely stem from your hypo-functioning of certain aspects of the brain that control exec functioning. The presentation of such symptoms in adulthood is frequently seen in the workplace and in the household and social arena. The key symptom clusters for the two children and adults are attention, activity and impulsivity. However, often the disorder can look unique from child to older and even person to person. Symptom Set of guidelines from the DSM-IV-TR:
a) Outward indications of inattention:
1) Fails to take into serious consideration details- tends to rush and infrequently makes careless mistakes
2) Difficulty sustaining attention tends to own poor concentration, difficulty commencing and completing tasks, and habit to get off task simply
3) Does not appear to listen- can “zone out” while in conversations with others and may even not realize it, hence losing important bits of details
4) Struggles to follow by means of on instructions- poor attentive skills and memory play a role in difficulty following directions
5) Difficulty with the organization- usually has poor time supervision and is often late, usually has a messy, disorganized as well as cluttered area in home/workplace/car.
6) Avoids as well as dislikes tasks that require intellectual effort- tends to procrastinate
7) Easily distracted
8) Negligent in daily activities- typically misses deadlines and commitments along with important events or date ranges. Often losing or misplacing things such as keys, phones, costs, work
b) Symptoms of Hyperactivity/ Impulsivity:
1) Fidgets together with hands, feet/legs, objects- can happen to have nervous energy, sleepless or anxious
2) Problems remaining seated- tends to sate easily
3) Runs/climbs excessively- The highly energetic, “climbing-up-the-walls” energy commonly seen in years as a child settles down by the middle teenage years. In late young adults and adults ‘hyperactivity’ is way more subtle
4) Difficulty in stepping into activities quietly- tends to want excitement
5) Acts as in the event-driven by a motor- will have more risk-taking behaviour, operates recklessly
6) Talks excessively- tends to have racing feelings, states mind doesn’t turn off, hyperactivity of the mind
7) Blurts out answers just before questions have been completed-difficulty curbing one’s actions
8) Offers difficulty waiting or having turns- poor patience
9) Interrupts or intrudes upon others- poor self-control makes improper comments
A certain number of signs or symptoms need to be present in 2 or higher settings- work, home, institution, etc. The symptoms must also produce a functional impairment in an individual setting.
Is adult AD/HD on the rise, and if so, precisely why?
Adult ADHD is becoming extensively recognized and more people are also been diagnosed than before, however, it is likely a function of far more acceptance and consensus on how the disorder can occur in adult life. As well as better screening methods with improved detection as well as treatment options. Adult ADHD continues to be largely under-reported and under-diagnosed.
If an adult thinks he may have ADHD, who ought he sees for a diagnosis/treatment?
Where a child can see a pediatrician or a Child as well as Adolescent Psychiatrist for analysis and treatment, an adult ought to see a mental health professional or Psychiatrist. Psychiatrists are specifically trained and likely have more encounters in recognizing symptoms of ATTENTION DEFICIT HYPERACTIVITY DISORDER, diagnosing ADHD, and are much more familiar with available treatments intended for Adult ADHD.
Additionally, a grown-up who suspects ADHD may wish to find a Psychiatrist who has teaching or experience in cooperating with children and adolescents- mainly because these subspecialists have the most teaching and experience with the dysfunction. Once diagnosed, the treatment is usually multifactorial and best executed through a team approach using professionals such as Psychiatrists for you to prescribe medications and Objective or other trained counsellors/therapists to provide cognitive-behavioural therapy along with skills training to learn sensible solutions to everyday problems.
Do you know the treatment options for adult ATTENTION DEFICIT HYPERACTIVITY DISORDER? Do all adults identified as having ADHD need medication? Will, certainly they need to take medication for a lifetime?
Treatment options are often the same with regard to adults as in children, as well as typically consist of a combination of treatment, lifestyle adjustments, and medicines. Therapies include behavioural adjustments and skills training to handle the core deficiencies associated with ADHD including- organization, arranging, time management, memory along with impulsivity. Important lifestyle conditions that need to be addressed and revised are adequate sleep, proper diet, and regular physical activity. Prescription drugs target these symptoms chemically and they are very effective.
According to the DSM-IV, in order to meet the diagnostic criteria intended for ADHD, symptoms should bring about “social, occupational or efficient impairment”, therefore medications could possibly be indicated especially if the therapy in addition to lifestyle changes doesn’t affect considerably improvement. Adults on remedies may be able to be more successful in the office and with their family/social life and be better able to use all their ADHD management skills to manufacture a better routine and construction for their life.
Depending on the seriousness of symptoms and the accomplishment of incorporating the skills of exercising into one’s daily life, it is easy to come off medications. Medications are only one piece of the treatment problem. Since there is no “cure” for ATTENTION DEFICIT-HYPERACTIVITY DISORDER, some form of treatment will always be necessary, however, it may be as simple as keeping organized and getting adequate sleep.
Some adults may possibly say that they’ve made it this specific far w/o needing remedy. Why start now? How might with no treatment ADHD affect a person’s lifetime?
It is possible not to need “treatment” consisting of medications; however, it can be unlikely that no portion of treatment will be needed. Many adults with ADHD could possibly be managing their symptoms instead of really knowing it. Just how many times have we been told, “if I don’t get ample sleep, I can’t think straight”, or “if it doesn’t get in my planner, it doesn’t exist”, or “I need my very own double shot espresso early in the day to get me focused” (caffeine is a weak stimulant)- definitely not saying that everyone does anyone says and does these things has ATTENTION DEFICIT-HYPERACTIVITY DISORDER, but some who are aware of their particular issues maybe managing signs in various fashions?
Also, particular environments may be more good at managing the condition than others. I have come across many young adult individuals who were valedictorians of their tiny highly structured high school school, however, upon entering a huge university with less construction and guidance, they get started having more problems with the lending brokers, and meeting deadlines and instructional performance.
It is not that they all of the sudden “caught” ADHD; the ailment was likely present to some amount since childhood, however a new experience in the environment caused indicators to be problematic enough to help cause functional impairment.
I’ve truly heard similar situations happen in work settings as well. In the event functional impairment exists, you’ll want to discuss treatment options with intellectual health professionals and your physician. Correctly shown that people with neglected ADHD are more likely to experiment/ “self-medicate” with substances, more likely to end up being unemployed, more likely to divorce and possess relational issues and more apt to be involved in motor vehicle accidents.
We have read that people with ATTENTION DEFICIT-HYPERACTIVITY DISORDER often have other mental health conditions like depression or stress and anxiety. Please tell me more about the bond.
People diagnosed with ADHD may have other mental health and fitness diagnoses as well, in some studies 6x as likely. The reasons behind this are multi-factorial. They could be due to chemical pathways and also “wiring” in the brain- ATTENTION DEFICIT/HYPERACTIVITY DISORDER often seen with finding out disabilities in children, esp. for reading. Other diseases can occur because the untreated ATTENTION DEFICIT/HYPERACTIVITY DISORDER symptoms put them at risk to get other disorders- i. Elizabeth. a child with ADHD who might be extremely hyperactive may be more prone to be abused and consequently develop anxiety from the stress.
I often see issues like depression and anxiousness to be the primary reason you can seek treatment- esp. in older adults and older teens. It doesn’t untreated ADHD symptoms which could lead to repeated failures, weak performance (at home, institution, work), and strained romantic relationships which, depending on how historical, can lead to frustration, irritability plus low self-worth. Over time this kind of stress and thought habits can lead to serious depression.
From time to time, it appears that untreated ADHD could mimic symptoms of depression and by treating the ADHD, a single start to do better, attain more, get praise along with improving self-esteem the depression symptoms is also treated. If depressive symptoms or disorders are actually co-occurring, it may be necessary to deal with both issues.
Is there a hereditary link to ADHD? If your kid has it, does that mean you may have it and not recognize this?
There is a strong genetic hyperlink to ADHD as well as other mental wellness disorders. Acad. to Doctor Biederman and research through Massachusetts General Hospital, in case a child has ADHD there, exists a five-fold increase in the risk of some other family members (1). Genetic hyperlinks are also discovered by doing double (identical vs fraternal) studies. Similar twins have the same DNA, cordial twins have DNA similar to what another sibling would talk about.
In one such study, Doctor Florence Levy and your ex-colleagues studied 1, 938 families with twins along with siblings in Australia. That they found that ADHD has an exceptionally high heritability as compared with other behavioural disorders. That they reported an 82 pct concordance rate for AD/HD in identical twins as compared with a 38 per cent attache rate for ADHD throughout nonidentical twins.
Read also: How to get a Good Counsellor and Psychotherapist | {
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-7,827,452,416,395,254,000 | Action of Molecular Switches in GPCRs - Theoretical and Experimental Studies | Bentham Science
Action of Molecular Switches in GPCRs - Theoretical and Experimental Studies
Author(s): B. Trzaskowski, D. Latek, S. Yuan, U. Ghoshdastider, A. Debinski, S. Filipek.
Journal Name: Current Medicinal Chemistry
Volume 19 , Issue 8 , 2012
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Abstract:
G protein coupled receptors (GPCRs), also called 7TM receptors, form a huge superfamily of membrane proteins that, upon activation by extracellular agonists, pass the signal to the cell interior. Ligands can bind either to extracellular N-terminus and loops (e.g. glutamate receptors) or to the binding site within transmembrane helices (Rhodopsin-like family). They are all activated by agonists although a spontaneous auto-activation of an empty receptor can also be observed. Biochemical and crystallographic methods together with molecular dynamics simulations and other theoretical techniques provided models of the receptor activation based on the action of so-called “molecular switches” buried in the receptor structure. They are changed by agonists but also by inverse agonists evoking an ensemble of activation states leading toward different activation pathways. Switches discovered so far include the ionic lock switch, the 3-7 lock switch, the tyrosine toggle switch linked with the nPxxy motif in TM7, and the transmission switch. The latter one was proposed instead of the tryptophan rotamer toggle switch because no change of the rotamer was observed in structures of activated receptors. The global toggle switch suggested earlier consisting of a vertical rigid motion of TM6, seems also to be implausible based on the recent crystal structures of GPCRs with agonists. Theoretical and experimental methods (crystallography, NMR, specific spectroscopic methods like FRET/BRET but also single-molecule-force-spectroscopy) are currently used to study the effect of ligands on the receptor structure, location of stable structural segments/domains of GPCRs, and to answer the still open question on how ligands are binding: either via ensemble of conformational receptor states or rather via induced fit mechanisms. On the other hand the structural investigations of homoand heterodimers and higher oligomers revealed the mechanism of allosteric signal transmission and receptor activation that could lead to design highly effective and selective allosteric or ago-allosteric drugs.
Keywords: 3-7 lock, 7TM receptors, allosteric, conserved motifs, dimerization, drug design, G-protein-coupled receptors, GPCRs, ionic lock, membrane receptors, molecular switches, receptor activation, signal transduction, transmission switch, tyrosine toggle switch
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Article Details
VOLUME: 19
ISSUE: 8
Year: 2012
Page: [1090 - 1109]
Pages: 20
DOI: 10.2174/092986712799320556
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5,910,145,939,155,161,000 | Journal of Chromatography B (v.867, #1)
Bovine and human hemoglobin (Hb) form the basis for many different types of Hb-based O2 carriers (HBOCs) ranging from chemically modified Hbs to particle encapsulated Hbs. Hence, the development of a facile purification method for preparing ultrapure Hb is essential for the reliable synthesis and formulation of HBOCs. In this work, we describe a simple process for purifying ultrapure solutions of bovine and human Hb. Bovine and human red blood cells (RBCs) were lyzed, and Hb was purified from the cell lysate by anion exchange chromatography. The initial purity of Hb fractions was analyzed by SDS-PAGE. Pure Hb fractions (corresponding to a single band on the SDS-PAGE gel) were pooled together and the overall purity and identity assessed by LC–MS. LC–MS analysis yielded two peaks corresponding to the calculated theoretical molecular weight of the alpha and beta chains of Hb. The activity of HPLC pure Hb was assessed by measuring its oxygen affinity, cooperativity and methemoglobin level. These measures of activity were comparable to values in the literature. Taken together, our results demonstrate that ultrapure Hb (electrophoresis and HPLC pure) can be easily prepared via anion exchange chromatography. In general, this method can be more broadly applied to purify hemoglobin from any source of RBC. This work is significant, since it outlines a simple method for generating ultrapure Hb for synthesis and/or formulation of HBOCs.
Keywords: Hemoglobin; Oxygen carrier; Blood substitute; Purification; Anion exchange chromatography; Ultrapure; SDS-PAGE; LC–MS; Red blood cell;
Determination of 8-iso-prostaglandin F in exhaled breath condensate using combination of immunoseparation and LC–ESI-MS/MS by Kamila Syslová; Petr Kačer; Marek Kuzma; Pavlína Klusáčková; Zdena Fenclová; Jindřiška Lebedová; Daniela Pelclová (8-14).
Rapid and precise method for the determination of 8-iso-prostaglandin F, an essential marker of the oxidative stress, in exhaled breath condensate (EBC) was developed. The protocol consisted of stable isotope dilution, immunoseparation combined with selective and sensitive LC–ESI-MS/MS operated in multiple reaction monitoring (MRM) mode. The imprecision of the developed method was below 8.8%, the parameter of mean inaccuracy was determined as <9.6% (0–250 pg of 8-iso-prostaglandin F/ml EBC). The limit of detection (LOD) was 1 pg/ml EBC and limit of quantification (LOQ) 5 pg/ml EBC. A significant difference in 8-iso-prostaglandin F content between the group of asbestosis patients and healthy volunteers was found.
Keywords: 8-iso-Prostaglandin F; Exhaled breath condensate; Immunoseparation;
Development and validation of a high-performance liquid chromatography method using diode array detection for the simultaneous quantification of aripiprazole and dehydro-aripiprazole in human plasma by Frédérique Lancelin; Kayssa Djebrani; Khalid Tabaouti; Linda Kraoul; Sophie Brovedani; Pascal Paubel; Marie-Liesse Piketty (15-19).
A high-performance liquid chromatography method with diode array detection (HPLC-DAD) was developed for quantification of aripiprazole and dehydro-aripiprazole, in human plasma. After a simple liquid–liquid extraction, chromatographic separation was carried out on a C18 reversed-phase column, using an ammonium buffer–acetonitrile mobile phase (40:60, v/v). The total run time was only 7 min at a flow-rate of 1.0 ml/min. The precision values were less than 12% and the accuracy values were ranging from 98 to 113% and the lower limit of quantification was 2 ng/ml for both compounds. Calibration curves were linear over a range of 2–1000 ng/ml. The mean trough plasma concentrations in patients treated with aripiprazole were 157 and 29 ng/ml for aripiprazole and dehydro-aripiprazole, respectively.
Keywords: Aripiprazole; Dehydro-aripiprazole; HPLC; Therapeutic drug monitoring;
Quantification of doripenem in human plasma and peritoneal fluid by high-performance liquid chromatography with ultraviolet detection by Kayo Ikeda; Kazuro Ikawa; Norifumi Morikawa; Keiko Kameda; Nami Urakawa; Hiroki Ohge; Taijiro Sueda (20-25).
A simple and rapid HPLC method that includes ultrafiltration to remove plasma and peritoneal fluid protein was developed to determine doripenem concentrations in human plasma and peritoneal fluid. Doripenem was stabilized by immediate mixing of the plasma or peritoneal fluid with 1 M 3-morpholinopropanesulfonic acid buffer (pH 7.0) (1:1). Doripenem and an internal standard were detected by measuring their ultraviolet absorbance at 300 nm. The calibration curves for doripenem in human plasma and peritoneal fluid were linear from 0.05 to 100 μg/mL. For plasma, both the intra- and the interday precision were less than 3.41% (CV), and the accuracy was between 97.4 and 101.7% above 0.05 μg/mL. For peritoneal fluid, the intra- and the interday precision were less than 2.98% (CV), and the accuracy was between 94.4 and 103.9% above 0.05 μg/mL. The limit of detection was 0.02 μg/mL in both plasma and peritoneal fluid. The assay has been applied to the therapeutic drug monitoring of doripenem in both plasma and peritoneal fluid.
Keywords: Doripenem; Ultrafiltration; HPLC; Plasma; Peritoneal fluid; Pharmacokinetic studies;
Urinary trans,trans-muconic acid (t,t-MA), a biomarker of benzene exposure, is usually determined by HPLC methods with detection by either UV or, more recently, electrospray tandem mass spectrometry. However, not all these methods have been fully validated for quantitative analysis. This paper presents an HPLC/MS/MS method for reliable quantitative determination of t,t-MA that uses a commercial deuterium-labeled isotope as internal standard; the matrix effect has been evaluated and LOD is 0.22 μg/L. We used this method to test 200 urine samples, 175 of them collected at end-of-shift from workers in an oil refinery.
Keywords: Biological monitoring; Trans,trans-muconic acid; HPLC/MS/MS; Method validation; Oil refinery workers;
A highly sensitive high-performance liquid chromatographic method for the simultaneous analysis of 1,2,3,4-tetrahydroisoquinolines (TIQs) in the rat brain was developed. 1,2,3,4-Tetrahydroisoquinoline (TIQ), 1-methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTIQ) and 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1-BeTIQ) were derivatized with 4-(5,6-dimethoxy-2-phthalimidinyl)-2-methoxyphenylsulfonyl chloride to produce fluorescent sulfonamides. The labeling reaction was carried out at 50 °C for 15 min at pH 8.5. The fluorescent derivatives were separated on a reversed-phase column by gradient elution using (A) water–(B) acetonitrile/methanol (55:45) at 55 °C and detected by fluorescence measurement at 318 nm (excitation) and 398 nm (emission). The detection limits (signal-to-noise ratio = 3) were 8–9 fmol per injection. The relative standard deviations (n = 6) of TIQs were 2.6–10.5% and the recoveries were 87.6, 101.8 and 75.2%, respectively. The concentrations of TIQ, 1-MeTIQ and 1-BeTIQ in normal rat brains (n = 6) were 0.7 ± 0.3 (0.10 ± 0.04), 3.4 ± 1.5 (0.50 ± 0.22) and 1.3 ± 1.8 pmol/g (0.30 ± 0.41 ng/g), respectively.
Keywords: HPLC; Fluorometric detection; 4-(5,6-Dimethoxy-2-phthalimidinyl)-2-methoxyphenylsulfonyl chloride; 1,2,3,4-Tetrahydroisoquinolines; Brain;
Highly sensitive method for quantitative determination of bilirubin in biological fluids and tissues by Jaroslav Zelenka; Martin Leníček; Lucie Muchová; Milan Jirsa; Michal Kudla; Peter Balaž; Marie Zadinová; J. Donald Ostrow; Ronald J. Wong; Libor Vítek (37-42).
Unconjugated bilirubin (UCB) exhibits potent antioxidant and cytoprotective properties, but causes apoptosis and cytotoxicity at pathologically elevated concentrations. Accurate measurement of UCB concentrations in cells, fluids and tissues is needed to evaluate its role in redox regulation, prevention of atherosclerotic and malignant diseases, and bilirubin encephalopathy. In the present study, we developed and validated a highly sensitive method for tissue UCB determinations. UCB was extracted from rat organs with chloroform/methanol/hexane at pH 6.2 and then partitioned into a minute volume of alkaline buffer that was subjected to HPLC using an octyl reverse phase (RP) column. Addition of mesobilirubin as an internal standard corrected for losses of UCB during extraction. Recoveries averaged 75 ± 5%. The detection limit was 10 pmol UCB/g wet tissue. Variance was ±2.5%. When used to measure UCB concentrations in tissues of jaundiced Gunn rats, this procedure yielded UCB levels directly comparable to published methods, and accurately determined very low tissue bilirubin concentrations (≤40 pmol UCB/g tissue) in non-jaundiced rats.
Keywords: Bilirubin; Gunn rats; HPLC; Method of determination; Tissue bilirubin;
This work describes the determination of N3-methyladenine, N7-methylguanine and O 6-methylguanine adducts in dimethyl sulphate-treated salmon-testes DNA employing reversed-phase high performance liquid chromatography (RP-HPLC) with UV–vis detection, followed by mass-spectrometric verification using electrospray ionisation in positive mode ESI(+). Within validation parameters, accuracy, precision, calibration parameters, limit of detection (LOD) and quantitation (LOQ) as well as stability of standard stock solutions were tested and presented for UV/vis detection. The limit of detection (LOD) was found to be 0.1 ng/mL for N3-methyladenine and 0.2 ng/mL for both N7-methylguanine and O 6-methylguanine (S/N = 3). The limit of quantitation (LOQ) was found to be 0.5 ng/mL for all measured compounds, (S/N = 10). Quantitative results were obtained for each substance based on eight-point calibration. Intra- and inter-day precisions were within 1.73–6.96 and 2.26–7.58%, respectively, and correlation coefficients of calibration curves (R 2) ranged from 0.9992 to 0.9997. Relative proportion of N7-methylguanine was accounted for 61.53 ± 2.97% (R.S.D. = 4.8), N3-methyladenine for 38.19 ± 2.99% (R.S.D. = 9.6) and O 6-methylguanine for 0.29 ± 0.02% (R.S.D. = 5.1), respectively. The application of the above-mentioned techniques provides a valuable contribution for simultaneous determination of methylated DNA adducts, and may represent a suitable approach for similar monitoring/screening studies.
Keywords: N3-methyladenine; N7-methylguanine; O 6-methylguanine; DNA methylated adducts; Dimethyl sulphate; HPLC; LC–MS–ESI(+);
A sensitive liquid chromatography–electrospray ionization-tandem mass spectrometric (LC–ESI-MS–MS) method for the quantification of 17α-hydroxyprogesterone (17OHP) in human saliva has been developed and validated. The saliva was deproteinized with acetonitrile, purified using a Strata-X cartridge, derivatized with a highly proton-affinitive reagent, 2-hydrazinopyridine, and subjected to LC–MS–MS. Quantification was based on the selected reaction monitoring, and deuterated 17OHP was used as the internal standard. This method allowed the reproducible and accurate quantification of the salivary 17OHP using a 200-μl sample, and the limit of quantitation was 5.0 pg/ml. The developed method was applied to clinical studies. A linear relationship was found to be positive (r 2 = 0.975) between the blood 17OHP level and the salivary 17OHP level measured using the proposed method. The result from the salivary 17OHP measurement in patients with congenital adrenal hyperplasia demonstrated that the proposed method is very useful for monitoring of the therapeutic efficacy during hormone replacement therapy.
Keywords: 17α-Hydroxyprogesterone; Saliva; Liquid chromatography–electrospray ionization-tandem mass spectrometry; Derivatization; Congenital adrenal hyperplasia; Hormone replacement therapy;
Simultaneous measurement of tryptophan and related compounds by liquid chromatography/electrospray ionization tandem mass spectrometry by Kazuo Yamada; Takeshi Miyazaki; Tomoko Shibata; Nobumasa Hara; Mikako Tsuchiya (57-61).
We have expanded a liquid chromatographic–tandem mass spectrometric method that measures 3-hydroxykynurenine and 3-hydroxyanthranilic acid in addition to tryptophan and kynurenine both intra- and extracellularly. After reversed phase HPLC separation, the compounds were detected in the MS positive multiple reaction monitoring mode. We found a good linear response for each tryptophan metabolite. The lower limit of quantification for each compound ranged from 0.01 to 0.1 μM. The extraction efficiencies from spiked cell samples and culture medium ranged between 83 and 111% and the overall coefficient of variation of analyses was less than 7%. Using our method, we found tryptophan metabolites in the cells and the culture medium of LN229 human glioma cells were stimulated by interferon-γ, a known inducer of indoleamine 2,3-dioxygenase. The intracellular concentrations of kynurenine, 3-hydroxykynurenine and 3-hydroxyanthranilic acid were higher than those in the medium. This is the first report of a method for the simultaneous determination of tryptophan and its metabolic products both intra- and extracellularly.
Keywords: Tryptophan; Kynurenine pathway; LC/MS/MS; Electrospray ionization;
A simple method for obtaining transferrins from human plasma and porcine serum: Preparations and properties by Lin Wu; Jinhui Wu; Jian Zhang; Yuanyuan Zhou; Guoyan Ren; Yiqiao Hu (62-68).
A simple method was described for the purification of serum transferrin (Tf) from human plasma and porcine serum with relative high yield and purity. The properties including purity, integrity, immunoreactivity and the receptor-binding ability of the proteins were studied by several assays, comprising spectrometry, SDS-PAGE, HPLC, Western blotting, urea electrophoresis, mass spectrometry and cytometry. Analysis from all the different aspects manifested that the proteins were of high purity. The two kinds of Tfs appeared to be iron-saturated as confirmed by their absorbance spectra and urea-PAGE mobility. The specific spectra of absorption of the two Tfs were both at around 465 nm. The relative molecular weights of human Tf (hTf) and porcine Tf (pTf) were determined by SDS-PAGE and further identified by MAIDI-TOF mass spectrometry with a result of 79,707 and 79,258, respectively. Immunoblotting assay showed that pTf could react with the anti-human Tf monoclonal antibody with a less level compared to hTf. FACS assays of their binding activities to Tf receptor-positive cell (K562 cell line) indicated that pTf could be recognized by the hTf receptor and internalized into cells, with a slightly less efficacy than hTf. All special property studies demonstrated that pTf was similar to hTf in physical and chemical characteristics, which gave a hint that pTf could substitute for hTf in some kinds of researches, such as using hTf as a carrier in drug targeting system.
Keywords: Transferrin; Purification; Identification;
A concentrated mixture of gossypol, 6-methoxy-gossypol, and 6,6′-dimethoxy-gossypol was extracted from the root bark of St. Vincent Sea Island cotton with acetone. This extract was derivatized with R-(−)-2-amino-1-propanol to form diastereomeric gossypol Schiff's bases. Analytical-scale reverse-phase chromatography of these Schiff's bases produced six peaks, indicating separation of the enantiomeric forms of the three gossypol compounds. The elution order of the peaks was found to vary with the polarity of the mobile phase. The chromatography was scaled to a preparative level and was used to isolate each compound. After hydrolysis of the separated Schiff's bases, the original compounds were recovered by precipitation from solutions of diethyl ether, acetic acid, and water. Fifty injections yielded approximately 500 mg of each methoxy-gossypol enantiomer and 300 mg of each dimethoxy-gossypol enantiomer. Each compound was characterized for carbon and hydrogen content, optical rotation, UV–vis light absorption, and melting point. Standard curves were developed and were used to measure the concentration of each gossypol form in the root bark and dehulled seed of St. Vincent Sea Island cotton. In seed tissue, 48% of the gossypol compounds were methylated, and the (−)-optical form was found to be in a slight excess to the (+)-optical form (53–54%) for all three compounds. In root bark, 71% of the gossypol compounds were methylated, and the (+)-optical form was in excess to the (−)-optical form for all three compounds. However, in this tissue the extent of enantiomeric excess decreased with the degree of methylation, with 77% of the gossypol existing in the (+)-optical form and 59% of the 6,6′-dimethoxy-gossypol existing in the (+)-optical form.
Keywords: Cotton; Cottonseed; Gossypol; Secondary metabolites; Separation processes;
Analysis of amphetamine-type stimulants and their metabolites in plasma, urine and bile by liquid chromatography with a strong cation-exchange column-tandem mass spectrometry by Kenji Kuwayama; Hiroyuki Inoue; Tatsuyuki Kanamori; Kenji Tsujikawa; Hajime Miyaguchi; Yuko T. Iwata; Seiji Miyauchi; Naoki Kamo (78-83).
The aim of this work was to develop and validate a method for analysing amphetamine-type stimulants (ATSs) and their metabolites in plasma, urine and bile by liquid chromatography with a strong cation-exchange column-tandem mass spectrometry, and to apply it to the pharmacokinetic study of ATSs. 3,4-Methylenedioxymethamphetamine, methamphetamine, ketamine and their main metabolites, 4-hydroxy-3-methoxymethamphetamine, 3,4-methylenedioxyamphetamine, p-hydroxymethamphetamine, amphetamine and norketamine, were simultaneously quantified by the new method (50–5000 ng/ml). The coefficients of variation and the percent deviations for the eight compounds were in the range of 0.2 to 5.3% and −9.4 to +12.8%, respectively. The recoveries were over 90% in all biological samples tested. This method was effective for the separation and the identification of ATSs and their main metabolites having amine moieties in plasma, urine and bile, and was applicable to pharmacokinetic analysis of methamphetamine, ketamine and their main metabolites in biological samples. This analytical method should be useful for the pharmacokinetic analysis of ATSs.
Keywords: Methamphetamine; Amphetamine-type stimulant; Pharmacokinetics; Rat; LC–MS/MS; Strong cation-exchange column;
A simple and sensitive high-performance liquid chromatography (HPLC) assay for the analysis of CZ48, a potent anticancer candidate, and its active metabolite camptothecin (CPT) in mouse plasma was developed and validated. CZ44 was used as an internal standard (IS). The samples were injected onto a C18 Synergi Polar-RP column (4 μm, 150 mm × 4.60 mm) maintained at 30 °C. The identification of peaks showed high specificity. Shimadzu RF-10AXL fluorescence detector was used at the excitation and emission of 380 and 418 nm, respectively. The mean recoveries were 81.41 ± 0.035%, 86.00 ± 0.053% and 82.21 ± 0.020% for CZ48 and 76.01 ± 0.028%, 77.04 ± 0.042% and 85.93 ± 0.023% for CPT at three concentrations of 10, 100 and 900 ng/ml, respectively. The calibration curve was linear (r 2 = 0.9999) over CZ48 and CPT concentrations ranging from 5 to 1000 ng/ml and 10–1000 ng/ml (n = 6), respectively. The method had an accuracy of >95% and intra- and inter-day precision (RE%) of <1.2% and <2.2% for CZ48 and CPT, respectively, at three different concentrations (10, 100 and 900 ng/ml). The lower limit of quantification (LLOQ) using 0.1 ml mouse plasma was 10 ng/ml for CZ48 and 5 ng/ml for CPT. Stability studies showed that CZ48 and CPT were stable in mouse plasma after 4 h incubation at room temperature or after 1 month storage at −80 °C with three freeze/thaw cycles. The method reported is simple, reliable, precise and accurate and confirmed by the determination of plasma samples in the mice after oral administration of CZ48.
Keywords: Camptothecin; CZ48; Chromatography; HPLC; Quantification;
Quantitative analysis of natural cyclodextrins by high-performance liquid chromatography with pulsed amperometric detection: Application to cell permeation study by Tarja Toropainen; Pekka Jarho; Marko Lehtonen; Pekka Keski-Rahkonen; Heli Raatikainen; Tomi Järvinen (90-98).
Simple HPLC-PAD methods were developed for quantitation of cyclodextrins (CDs) in aqueous matrices from in vitro cell permeation studies. C-18 solid-phase extraction was used for sample pretreatment. Samples were analysed using acetonitrile–water mobile phase with post-column alkalization by 0.5 M NaOH. Zorbax SB-Aq (for α-CD) and Zorbax SB-Phenyl (for β-CD and γ-CD) columns gave excellent peak shape and sufficient resolution of CD to glucose (2.7–3.2). The methods showed good concentration–response relationship (r ≥ 0.999), precision (RSD% 0.7–5.1), repeatability (RSD% 3.4–13.7) and accuracy (87–107%). The limits of quantitation were 0.78, 0.46 and 0.52 μg/ml for α-CD, β-CD and γ-CD (RSD% of 10.6, 8.1 and 16.3, respectively).
Keywords: α-Cyclodextrin; β-Cyclodextrin; γ-Cyclodextrin; Quantitative analysis; High-performance liquid chromatography; Pulsed amperometric detection; Cell permeation;
Simultaneous determination of amitraz and its metabolite in human serum by monolithic silica spin column extraction and liquid chromatography–mass spectrometry by Takeshi Saito; Rie Yamamoto; Shigeaki Inoue; Izumi Kishiyama; Shota Miyazaki; Akihiro Nakamoto; Manami Nishida; Akira Namera; Sadaki Inokuchi (99-104).
A simple, rapid, sensitive, and specific liquid chromatography–mass spectrometry (LC–MS) method was developed and validated for the quantification of amitraz and its metabolite in human serum. Both the compounds were extracted using monolithic silica spin columns with acetonitrile. The chromatographic separation was performed on a reverse-phase C18 column with a mobile phase of 10 mM ammonium formate–acetonitrile. The protonated analyte was quantitated in positive ionization by mass spectrometry. The method was validated over the concentration range of 25–1000 ng/ml for amitraz and its metabolite in human serum. For both compounds, the limit of detection was 5 ng/ml. The method was applied to serum samples taken from an attempted suicide patient, and only small volumes of serum were required for the simultaneous determination of these compounds.
Keywords: Amitraz; Amitraz metabolite; Serum; Monolithic silica spin column; LC–MS;
A rapid and sensitive method was developed using high-performance liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) for the quantification of besifloxacin in human tears using sparfloxacin as the internal standard (IS). Besifloxacin was extracted from human tear samples using an ammonium formate buffer at pH 3.25. The method was validated over a concentration range of 2–2000 ng/mL, with a total run time of less than 4 min. The overall intra- and inter-day precision for this method was less than 6%. The method was used to measure besifloxacin concentrations in tear samples collected after topical ocular administration to humans; besifloxacin concentrations were 610 ± 540 μg/g (15 min) and 1.60 ± 2.28 μg/g (24 h).
Keywords: Besifloxacin; Fluoroquinolone; Antimicrobial agent; Human tears; LC/MS/MS; Pharmacokinetics;
Tacrolimus (FK506) is a potent immunosuppressant widely used for organ transplantation patients while diltiazem (DTZ), a calcium-channel inhibitor, is often used in renal transplantation patients to prevent post-transplant hypertension. However, DTZ has a significant pharmacokinetic interaction with FK506. In this study, a rapid and sensitive ammonium-adduct based liquid chromatography–tandem mass spectrometry (LC/MS/MS) method has been developed and validated for the simultaneous determination of FK506 and DTZ in human whole blood using ascomycin as the internal standard (IS). After extraction of the whole blood samples by ethyl acetate, FK506, DTZ and the IS were subjected to LC/MS/MS analysis using electro-spray positive-ion mode ionization (ESI+). Chromatographic separation was performed on a Hypersil BDS C18 column (50 mm × 2.1 mm, i.d., 3 μm). The MS/MS detection was conducted by monitoring the fragmentation of 821.7 → 768.9 (m/z) for FK506, 415.5 → 310.3 (m/z) for DTZ and 809.8 → 757.0 (m/z) for IS. The method had a chromatographic running time of approximately 2 min and linear calibration curves over the concentrations of 0.5–200 ng/mL for FK506 and 2–250 ng/mL for DTZ. The recoveries of liquid–liquid extraction method were 58.3–62.6% for FK506 and 50.4–58.8% for DTZ. The lower limit of quantification (LLOQ) of the analytical method was 0.5 ng/mL for FK506 and 2 ng/mL for DTZ. The intra- and inter-day precision was less than 15% for all quality control samples at concentrations of 2, 10, and 50 ng/mL for FK506 and 5, 25, and 100 ng/mL for DTZ. The validated LC/MS/MS method has been successfully used to analyze the concentrations of FK506 and DTZ in whole blood samples from pharmacokinetic studies in renal transplanted patients.
Keywords: Tacrolimus; Diltiazem; Liquid chromatography–tandem mass spectrometry; Pharmacokinetics; Renal transplant;
The N-terminus of the trimeric TNF-alpha molecule comprises two basic arginines within the short amino-acid sequence VRSSSR, which is here shown to be essential for binding of TNF-alpha to heparin–Sepharose. Mixed trimers containing full-length and ΔN6-truncated subunits revealed a single VRSSSR sequence to be sufficient to achieve binding. On the basis of this newly identified heparin-binding domain, a new method for efficient purification of TNF-alpha is described. Affinity chromatography on heparin–Sepharose was introduced as a key step for highly purified TNF-alpha at a high yield. With minor modifications, this procedure can be used for TNF-alpha analogues that have full-length N-termini, as shown for the less toxic analogue LK-805.
Keywords: Heparin-binding domain; TNF-alpha; Affinity chromatography;
LC–MS analysis of trimethoxyamphetamine designer drugs (TMA series) from urine samples by Maria Nieddu; Gianpiero Boatto; Maria Antonietta Pirisi; Emanuela Azara; Mauro Marchetti (126-130).
A sensitive liquid chromatography–mass spectrometric (LC–MS) method for quantification of an active psychedelic hallucinogenic drugs (trimethoxyamphetamines) in human urine after solid-phase extraction (SPE) with C18 cartridge was developed and validated. Chromatographic separation was achieved on reversed-phase Phenomenex 3.0 μm Polar Plus column (150 mm × 2.1 mm) with acetonitrile −0.2% acetic acid as mobile-phase and the step gradient elution resulted in a total run time of about 20 min. The analytes were detected by using an electrospray positive ionization mass spectrometry in selected ion monitoring (SIM) mode. In the evaluated concentration range (10–200 ng/mL) (R 2 ≥ 0.998) a good linear relationship was obtained. The lower limits of detection (LLODs) and quantification (LLOQs) ranged from 4.26 to 9.12 ng/mL and from 13.18 to 29.22 ng/mL, respectively. Average recoveries ranged from 68.52 to 97.90% in urine at the concentrations of 25, 50 and 100 ng/mL. Intra- and inter-day relative standard deviations were 3.70–10.77% and 7.63–12.94%, respectively. This LC–MS method proved to be robust and reliable, and suitable for the use as a confirmation method in clinical urine drug testing.
Keywords: TMA series; Trimethoxyamphetamines; Designer drugs; Human urine; Liquid chromatography; Mass spectrometry;
Ultra-performance liquid chromatography–tandem mass spectrometric method for the determination of Artemisinin in rat serum and its application in pharmacokinetics by Lie Li; Deepthi Pabbisetty; Paulo Carvalho; Mitchell A. Avery; John. S. Williamson; Bonnie A. Avery (131-137).
A rapid and sensitive ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to quantify artemisinin in rat serum. The lower limit of quantification (LLOQ) was 4 ng/mL. The calibration curve was linear from 4 ng/mL to 10,000 ng/mL (R = 0.998). The assay was based on the selected reaction monitoring (SRM) transitions at m/z 305.4–151.10 for artemisinin and m/z 335.2–163.10 for arteether (internal standard). The artemisinin and internal standard can be separated from endogenous interferences in rat serum. Inter- and intra-day assay variation was less than 15%. The extraction recoveries ranged from 80.0 to 107.3% at the three concentrations (5000, 2000, and 200 ng/mL). This method was successfully applied to pharmacokinetic studies of artemisinin after intravenous and oral administration to rats.
Keywords: Artemisinin; UPLC; MS/MS; Pharmacokinetic; Rat serum;
The quantitative determination of caffeic acid phenethyl ester (CAPE) and its fluorinated derivative (FCAPE) from rat plasma using ultra-performance liquid chromatography with electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) is reported. CAPE and FCAPE were extracted using ethyl acetate in the presence of methyl caffeate (MC) as internal standard. Separation was achieved using a C18 column (2.1 mm × 50 mm, 1.7 μm) and gradient elution with water and acetonitrile containing 0.2% and 0.1% formic acid, respectively. A non-linear response over a broad concentration range (1–1000 ng/ml, r 2 > 0.995 using a quadratic regression model and 1/concentration weighting) was obtained. The inter-day and intra-day variability for CAPE and FCAPE were found to be less than 14.2% and 9.5%, respectively. Data are presented to illustrate the practicality of the method for the pharmacokinetic evaluation of CAPE and FCAPE after intravenous administration to rats.
Keywords: Caffeic acid phenethyl ester; Fluorinated caffeic acid phenethyl ester; Rat blood plasma; UPLC-ESI-MS/MS;
A simple and sensitive HPLC/MS/MS method was developed and evaluated to determine the concentration of ritodrine (RTD) in human plasma. Liquid–liquid extraction with ethyl acetate was employed as the sample preparation method. The structural analogue salbutamol was selected as the internal standard (IS). The liquid chromatography was performed on a Hanbon Sci. & Tech. Lichrospher CN (150 mm × 4.6 mm, i.d., 5 μm) column (Hanbon, China) at 20 °C. A mixture of 0.03% acetic acid and methanol (50:50, v/v) was used as isocratic mobile phase to give the retention time 3.60 min for ritodrine and 2.94 min for salbutamol. Selected reaction monitoring (SRM) in positive ionization mode was employed for mass detection. The calibration functions were linear over the concentration range 0.39–100 ng mL−1. The intra- and inter-day precision of the method were less than 15%. The lower limit of quantification was 0.39 ng mL−1. The method had been found to be suitable for application to a pharmacokinetic study after oral administration of 20 mg ritodrine hydrochloride tablet to 18 healthy female volunteers. The half-life is 2.54 ± 0.67 h.
Keywords: Ritodrine; Electrospray ionization tandem mass spectrometry; Determination; Human plasma;
A highly sensitive and fast reversed-phase liquid chromatographic (LC) method combined with pulsed electrochemical detection (PED) was developed for the direct quantification of the aminoglycoside antibiotic amikacin in cerebrospinal fluid (CSF). The limit of quantification obtained was 0.06 μg/ml and linearity was established over the concentration range 0.06–4.00 μg/ml. The recovery was found to be close to 100%. This method was developed in order to study CSF pharmacokinetics of amikacin in neonates. The narrow therapeutic range calls for monitoring to ensure optimal therapy and to minimize the risk of toxic side effects such as nephro- and ototoxicity, especially in populations like preterm neonates at birth, where the predictability of amikacin clearance is limited. Typical problems to be solved were the low amikacin concentrations and the limited sample volume of CSF.
Keywords: Amikacin; Cerebrospinal fluid; Pulsed electrochemical detection; Reversed-phase liquid chromatography;
A 96-well protein precipitation, liquid chromatography–tandem mass spectrometry (LC–MS/MS) method has been developed and fully validated for the determination of fudosteine in human plasma. After protein precipitation of the plasma samples (50 μL) by the methanol (150 μL) containing the internal standard (IS), erdosteine, the 96-well plate was vortexed for 5 min and centrifuged for 15 min. The 100 μL supernatant and 100 μL mobile phase were added to another plate and mixed and then the mixture was directly injected into the LC–MS/MS system in the negative ionization mode. The separation was performed on a XB-CN column for 3.0 min per sample using an eluent of methanol–water (60:40, v/v) containing 0.005% formic acid. Multiple reaction monitoring (MRM) using the precursor-product ion transitions m/z 178 → 91 and m/z 284 → 91 was performed to quantify fudosteine and erdosteine, respectively. The method was sensitive with a lower limit of quantification (LLOQ) of 0.02 μg mL−1, with good linearity (r > 0.999) over the linear range of 0.02–10 μg mL−1. The within- and between-run precision was less than 5.5% and accuracy ranged from 94.2 to 106.7% for quality control (QC) samples at three concentrations of 0.05, 1 and 8 μg mL−1. The method was employed in the clinical pharmacokinetic study of fudosteine formulation product after oral administration to healthy volunteers.
Keywords: Fudosteine; LC–MS/MS; 96-Well protein precipitation; Pharmacokinetics;
Zinc-decorated silica-coated magnetic nanoparticles for protein binding and controlled release by Marjan Bele; Gorazd Hribar; Stanislav Čampelj; Darko Makovec; Vladka Gaberc-Porekar; Milena Zorko; Miran Gaberšček; Janko Jamnik; Peter Venturini (160-164).
The aim of this study was to be able to reversibly bind histidine-rich proteins to the surface of maghemite magnetic nanoparticles via coordinative bonding using Zn ions as the anchoring points. We showed that in order to adsorb Zn ions on the maghemite, the surface of the latter needs to be modified. As silica is known to strongly adsorb zinc ions, we chose to modify the maghemite nanoparticles with a nanometre-thick silica layer. This layer appeared to be thin enough for the maghemite nanoparticles to preserve their superparamagnetic nature. As a model the histidine-rich protein bovine serum albumin (BSA) was used. The release of the BSA bound to Zn-decorated silica-coated maghemite nanoparticles was analysed using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). We demonstrated that the bonding of the BSA to such modified magnetic nanoparticles is highly reversible and can be controlled by an appropriate change of the external conditions, such as a pH decrease or the presence/supply of other chelating compounds.
Keywords: Magnetic nanoparticles; Silica coating; Zinc adsorption; Histidine affinity binding; Protein binding; Protein nanoparticles; Coordinative binding; | {
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Aortic stenosis. Notes and a case (VIDEO): A patient with aortic stenosis and left ventricular dysfunction
IMPORTANT NOTE : THE SITE IS UNDER DEVELOPMENT AND CONTENTS ARE CONTINUOUSLY ADDED.
A cardiology case (VIDEO) A male patient 82 years old with a systolic heart murmur of Aortic Stenosis.
The patient has a systolic murmur of aortic stenosis. The second heart sound is not audible which is an indication of severe aortic stenosis. The ECG shows signs of left ventricular hypertrophy: increased Sokolow index and ST- T wave abnormalities with typical morphology of left ventricular strain. Echo shows concentric left ventricular hypertrophy with moderate left ventricular systolic dysfunction : here ejection fraction EF is about 40% . There is severe stenosis of the aortic valve : here peak velocity is 5 m/s, and mean pressure gradient is 75 mm Hg- A peak velocity at least 4 m/s and a mean gradient at least 40 mmHg are considered as accurate indications of severe aortic stenosis. There is also moderate mitral regurgitation, and a dilated left atrium. In transmitral flow: E wave> A wave, but this cannot be a normal pattern, because of the following reasons : The patient obviously has diastolic dysfunction, since there is systolic dysfunction: because diastolic dysfunction generally precedes systolic dysfunction. Left ventricular hypertrophy and a dilated left atrium, are other factors favouring diastolic dysfunction in this patient.. So the pattern of transmitral flow is pseudonormal, also named "grade II systolic dysfunction" . Pseudonormal pattern is accompanied by an elevated left ventricular diastolic pressure. The patient has an indication for intervention. Main , class I , indications for intervention in severe aortic stenosis, AS, are the following : 1. Severe AS and any symptoms related to AS. 2. Severe AS in patients undergoing CABG, surgery of the ascending aorta or another valve. 3. In asymptomatic patients with severe AS and systolic left ventricular dysfunction :EF <50%, not due to another cause. 4. In asymptomatic patients with severe AS and abnormal exercise test showing symptoms on exercise clearly related to AS. Our patient is asymptomatic, but has left ventricular dysfunction probably caused by the severe AS. So there is an indication for intervention,valve replacement, but because of his age and risk factors, any such intervention must be preceded by coronary angiography. The STS mortality risk score ,Society of Thoracic Surgeons mortality risk score for cardiac operation, for this patient favours surgery. So surgery seems to be a better choice according to the current guidelines, over transcatheter aortic valve implantation,TAVI for the given patient : TAVI is generally preferred for patients with especially high surgical risk: STS mortality risk score of at least 10 % ,or when using an other mortality scoring system : A logistic EuroSCORE ≥20%. This patient has a calculated STS mortality risk score of about 3 % The decision has to be made by a heart team ,cardiologists and cardiac surgeons, and there are also other factors taken into account. The heart team may decide that TAVI is a better option for a given patient, even if the risk score shows intermediate surgical risk, with STS mortality score 4-10%, if there are other concerns , based upon the results of the patent's clinical findings and workup.
Aortic stenosis
NOTES
Aortic stenosis is a disease in which progressive obstruction to
left ventricular outflow results in the following: 1) concentric hypertrophy of the left ventricle, due to pressure overload, 2) symptoms of angina, dyspnea, and syncope; and 3) if severe and untreated, it can lead to sudden cardiac death.
Etiology of aortic stenosis
Anatomically it can be divided into supravalvular aortic stenosis, fixed subvalvular aortic stenosis, and valvular aortic stenosis, which is the most common form.
Valvular aortic stenosis has many causes, including senile degenerative disease (which is the most common cause and occurs in elderly individuals), congenital bicuspid (one of the common causes especially in young people and in middle-aged people due to progressive degeneration of the valve), congenital unicuspid aortic valve (rare) and rheumatic heart disease (common in developing countries). Bicuspid aortic valves occur in 1-2% of the population and are often associated with dilation of the ascending aorta.
Echocardiography (two-dimensional and Doppler) can be used to determine the level of obstruction and to assess its severity.The pathophysiologic processes of aortic stenosis result from
1) An increase in afterload, which causes increased cardiac work, progressive left ventricular hypertrophy, and increased myocardial oxygen demand.
2) A decrease in systemic and coronary blood flow from obstruction.
Myocardial ischemia occurs in patients with aortic stenosis, even if epicardial coronary arteries are normal, because of a mismatch in myocardial oxygen supply and demand.
These are the causes of the classic symptom triad of dyspnea (commonly exertional dyspnea even in patients with a normal systolic function), angina, and syncope, that can develop in severe aortic stenosis. Abnormalities of diastolic function (due to left ventricular hypertrophy and ischemia) are common in patients with aortic stenosis and cause increased left ventricular filling pressures that can be reflected onto the pulmonary circulation.
The clinical presentation of aortic stenosis
The clinical presentation of patients with aortic stenosis can be variable. Some patients are asymptomatic, and the diagnosis is suspected because of a systolic heart murmur, detected on physical examination. Others have one or more symptoms from the aforementioned classic triad. Sudden death may be the initial manifestation of aortic stenosis, although this is rare.
On physical examination, the characteristics of the murmur of aortic valvular stenosis are the following: Timing: Mid-systolic, Shape: crescendo-decrescendo (intensity rises and falls during systole). Location of maximal intensity: Right 2nd intercostal space, at the base of the heart. Radiation: Upward to the carotid arteries. Pitch: Low, Quality: Rough.
Is it possible to differentiate between the systolic murmur of valvular aortic stenosis (AS) and the systolic murmur of hypertrophic obstructive cardiomyopathy (HOCM) with maneuvers affecting cardiac preload?
Yes. Preload is the quantity of blood returning to the heart through the veins. Maneuvers that decrease preload, such as taking the standing position, or the straining phase of the Valsalva maneuver decrease the volume of blood ejected through the stenotic valve and so they decrease the intensity of the murmur of AS.
In HOCM, a decreased preload (venous return) causes a decrease in cardiac filling and left ventricular volume and so it results in a transient increase in the severity of the dynamic obstruction in the left ventricular outflow tract. This increases the intensity of the murmur in HOCM. The opposite effects are observed with maneuvers that increase preload, such as squatting and the release phase (the termination) of the Valsalva maneuver. Then in AS the murmur increases in intensity and in HOCM the murmur intensity decreases.
Severe aortic stenosis is characterized by a dampened (slow and of reduced magnitude) upstroke of the carotid artery pulse, a late-peaking systolic ejection murmur of large duration, an aortic component of the second heart sound (A2) which is absent or reduced and a sustained left ventricular impulse. The duration of the murmur and the timing of its peak correspond better to the stenosis severity than its intensity.
Echocardiography in aortic stenosis
Two-dimensional echocardiography can show the location (valvular, subvalvular, or supravalvular) and the cause of the obstruction. Doppler echocardiography is efficient for assessing the severity of aortic stenosis, which cannot be judged on the basis of the 2-dimensional image alone. Echocardiographic criteria for the determination of the severity of aortic stenosis: Moderate aortic valvular stenosis is characterized by a mean gradient of 25-40 mmHg and a valve area (calculated with the continuity equation) of 1-1.5 cm2
Mild aortic stenosis is characterized by a mean gradient which is less than these values and a valve area greater than these values.
Severe aortic valvular stenosis is diagnosed when the mean gradient is >40, but ≤80 mmHg and valve area ≥0.7 but <1 cm2
(or valve area indexed to body surface area <0.6 cm2 /m2 but this calculation is only used for individuals with a small body size).
Critical (=very severe) aortic stenosis: mean gradient >80 and valve area <0.7
cm2. It is important to calculate the aortic valve area and the method to perform this calculation is discussed below:
How to calculate the aortic valve area
The aortic valve area (AVA) is calculated by applying the continuity equation. According to this principle, since blood flow is continuous, the volume of blood ejected through the left ventricular outflow tract (LVOT) equals the volume of blood that crosses the aortic valve: AVA x VTIAoV = CSALVOT x VTILVOT
Solving for AVA, yields: AVA = CSALVOT x VT I LVOT/VTIAoV.
CSALVOT is the cross sectional area of the LVOTThe LVOT is concidered as having a circular cross section, and so if r is the radius of the LVOT and D= the diameter of the LVOT=2rthe CSALVOT is calculated:
CSALVOTπr=3,14r=3,14(D/2)2 =3,14 D2/4= 0,785D2
VTI is the time velocity integral (calculated by the machine as the area under the curve of the doppler velocity signal). VT I LVOT is the time velocity integral of the flow through the LVOT during systole (the pulse wave doppler signal of the flow through the LVOT is used for this measurement). VTIAoV is the time velocity integral of the flow through the aortic valve (AoV) during systole (the continuous wave doppler signal of the flow through the AoV is used for this measurement).
You should index AVA to body surface area (BSA) if the patient is at extremes of body habitus (very small, or very large body weight).
As mentioned above, severe aortic stenosis is characterized by:
AVA <1 cm2, AVA/BSA <0.6 cm2/m2
The dimensionless index
The dimensionless index is a ratio of velocities or VTIs of the LVOT and the aortic valve, that does not require measurement of the diameter of the LVOT (which is a frequent source of error):
LVOT peak velocity or VTI divided by the AoV peak velocity or VTi.
In severe AS this ratio is <0.25 whereas in mild AS >0.5.
Low flow- low gradient (LF-LG) aortic stenosis (AS) with a low left ventricular ejection fraction (LVEF)
Low flow-low gradient (LF-LG) aortic stenosis (AS) with a reduced left ventricular ejection fraction (EF) is observed in approximately 5% -10% of patients with aortic stenosis. The diagnosis and treatment of these patients is challenging. This condition is characterized by the combination of an aortic valve area compatible with severe aortic stenosis (AS) <1.0 cm2 , or < 0.6 cm2 /m2, but a relatively low mean transvalvular gradient (i.e., <40 mm Hg), and a low left ventricular ejection fraction ( LVEF) <50 % and a low flow state (i.e., stroke volume index <35 ml/m2 and/or cardiac index <3.0 L/min/m2). The stroke volume index is the stoke volume divided by the body surface area. The stroke volume is the volume of blood ejected by the left ventricle through the LVOT and the aortic valve in systole and is calculated as CSALVOT x VTI LVOT.
The low flow state is the result of the left ventricular (LV) systolic dysfunction. The LV systolic dysfunction can be the result of an increased afterload due to the aortic stenosis (AS) itself, or it can be the consequence of a primary myocardial disease with a coexisting AS.
The diagnostic problem in low flow-low gradient AS with a low LVEF is to distinguish true severe AS from pseudosevere AS. In pseudosevere aortic stenosis, there is a moderate or mild stenosis of the valve, but the low flow state causes incomplete opening of the aortic valve and thus the calculated valve area appears to be significantly reduced.
The distinction between true severe AS from pseudosevere AS is required for therapeutic decision-making. Patients with true severe aortic stenosis (AS) generally benefit from aortic valve replacement, but in those with pseudosevere AS, aortic valve replacement is not indicated.
Low-dose (5-20 μg/kg/min) dobutamine stress echocardiography (stress echo) is helpful in distinguishing true severe AS from pseudosevere AS and for the assessment of the left ventricular contractile reserve (also called "LV flow reserve").
For this purpose, longer stress-echo stages (5-8 min) should be used. This enables measurements to be acquired once the heart rate and hemodynamics have reached a steady state.
During dobutamine stress echo in patients with true severe aortic stenosis (AS) there is no marked increase in the calculated aortic valve area, which remains <1.2 cm2 , but the mean transvalvular gradient increases and reaches a level of ≥40 mmHg.
In patients with pseudosevere AS, in dobutamine stress echo there is a mean gradient < 40 mm Hg (at peak stress), a peak stress aortic valve area >1.2 cm2, and/or an increase in valve area of 0.3 cm2. The prevalence of pseudosevere AS is 20%-35%.
In cases of indeterminate AS severity (when there is a discordance between aortic valve area and mean gradient measurements during stress echo) the MDCT AoV Ca score is assessed. This is a score showing the severity of aortic valve calcification obtained by multidetector computed tomography (MDCT). The presence of an MDCT AoV Ca score >1200 in women and >2000 in men indicates true severe aortic stenosis, whereas with lower scores the stenosis is characterized as pseudosevere.
The assessment of the left ventricular flow reserve (also known as "contractile reserve") by stress echocardiography, provides information about operative risk. LV flow reserve is present when there is an increase in stroke volume of 20% during dobutamine stress echo.
An inadequate LV flow reserve predicts a high operative risk but does not predict a lack of recovery of the left ventricular (LV) function, or a lack of improvement in symptomatic status, and late
survival after the operation. The absence of LV flow reserve should not preclude consideration of aortic valve replacement in patients with low flow-low gradient AS, if the valvular stenosis is true-severe, but it is a predictor of an increased operative risk. Patients with no LV flow reserve who survive the operation, demonstrate a postoperative improvement in LVEF, symptoms, and the late survival rate, which is comparable to those in patients with flow reserve. Thus patients with no flow reserve (no contractile reserve), but true severe AS, who survive after aortic valve replacement have a much better course than patients with severe AS and no flow reserve receiving only medical (drug) treatment.
Patients with true-severe AS, if flow reserve is present (a rise in stroke volume ≥ 20% in stress echo) are usually managed with surgical aortic valve replacement.
Patients with true-severe AS, if flow reserve is not present also need aortic valve replacement, but they have a high operative mortality. Thus, in these patients, usually transcatheter aortic valve replacement (TAVR, or TAVI) should be considered, although some can also be managed surgically.
Patients with pseudosevere AS are managed medically (medical treatment for heart failure with reduced |EF).
Paradoxical low flow-low gradient aortic stenosis,with preserved LVEF
The assessment of patients with aortic stenosis (AS), sometimes becomes complicated by discordant echocardiographic findings, such as the combination of a small aortic valve area <1.0 cm2 consistent with severe AS and a low mean gradient (<40 mm Hg) indicative of non-severe AS. Such findings
raise uncertainty about the actual severity of the aortic stenosis (AS) and the potential indication of aortic valve replacement if the patient has symptoms. Discordance between the calculated aortic valve area (small) and the gradient (low) is often the result of low left ventricular outflow because even a modest decrease in flow can produce a significant reduction in the gradient. This may lead to an underestimation of stenosis severity.
Patients with true severe aortic stenosis (AS) may demonstrate a low gradient if there is a reduced flow through the aortic valve. This low-flow, low-gradient (LF-LG) aortic stenosis may occur in the context of either a reduced or preserved left ventricular ejection fraction (LVEF). A LF-LG aortic stenosis with a preserved (normal) LVEF, is called "paradoxical low flow-low gradient aortic stenosis".
Paradoxical low flow-low gradient (LF-LG) aortic stenosis is characterized by:
A small aortic valve area <1.0 cmor <0.6 cm2/mof body surface area
A low mean gradient ( <40 mmHg),
A low flow (stroke volume index <35 ml/m2), and
A preserved LVEF (≥ 50%).
The aortic valve is thickened and calcified, with reduced opening.
Doppler velocity index DVI is <0.25
There is a small left ventricular (LV) cavity size:
End diastolic diameter <47 mm/ end diastolic volume <55 mL/m2
Impaired LV filling (mitral inflow velocities and the diastolic mitral annular velocites show indications of significant diastolic dysfunction)
Global LV longitudinal strain is reduced, usually <15%
Paradoxical LF-LG aortic stenosis tends to occur more often in patients of older age, female gender, and with concomitant hypertension, diabetes, or metabolic syndrome. In paradoxical LF-LG aortic stenosis, the decrease in flow (stroke volume) is predominantly due to an impaired diastolic function (impaired LV filling), occuring in a ventricle of small internal dimensions and with concentric hypertrophy. A concomitant intrinsic systolic dysfunction is also present when more sensitive indices are examined, such as the peak mitral annular S velocity measured with tissue doppler, or peak left ventricular systolic longitudinal strain (percentage of LV shortening). This kind of "subclinical" systolic dysfunction also seems to contribute (to a lesser extent than the impaired LV filling) to a reduced stroke volume.
In patients with LF-LG aortic stenosis with preserved LVEF, besides significant LV diastolic dysfunction with reduced left ventricular compliance, several other factors may also contribute to the reduction of the flow rate through the aortic valve (low flow). Such factors are atrial fibrillation, reduced arterial compliance (arterial "stiffness" is common in older individuals), and concomitant dysfunction of other valves (mitral regurgitation or stenosis, or tricuspid regurgitation).
The assessment of the patient with paradoxical LF-LG aortic stenosis with preserved LVEF, includes several steps:
At first, one must carefully repeat the measurements, to exclude possible errors. A usual source of errors is at the measurement of the area of the left ventricular outflow tract (LVOT), which is multiplied by the TVI (time velocity integral) of the LVOT, in order to calculate stroke volume. The accuracy of the measurement of the LVOT diameter is very important. Moreover, a good practice is to measure the LVOT diameter at the base of the cusps of the aortic valve, where the LVOT has a more circular shape, instead of making the measurement below the aortic annulus, where the LVOT cross section is often elliptical. If no measurement error is identified and the echocardiographic examination is also concordant with the other features of this entity (e.g. concentric hypertrophy, a small LV, diastolic dysfunction, preserved EF, etc), then one must check if there is hypertension (which may have an effect on afterload and flow). The presence or absence of symptoms related to AS also plays an important role in the therapeutic decisions. If there are no symptoms the patient remains under frequent follow-up, but aortic valve replacement is not indicated. If there is hypertension, antihypertensive treatment is given and the patient is reassessed with echocardiography. If measurements still indicate paradoxical LF-LG aortic stenosis, after hypertension has been corrected, or in a patient with normal arterial blood pressure and the patient also has symptoms that can be attributed to AS, it is important to evaluate the true severity of the aortic stenosis (AS). This will guide further treatment. Thus, a normotensive patient with symptoms of AS and echocardiographic features of LF-LG aortic stenosis with preserved LVEF, will be tested with dobutamine or exercise stress echocardiography. This will distinguish pseudo-severe from severe AS. As in classical LF-LG aortic stenosis with a reduced LVEF, also in paradoxical LF-LG aortic stenosis with a preserved LVEF the stroke volume and the transvalvular flow rate is low. Thus, the flow may not be high enough to fully open the aortic valve and this may result in a lower calculated aortic valve area, in a valve which may be only moderately stenotic.
Exercise stress echocardiography can confirm the presence of symptoms and assess the response of the aortic valve area and the gradient to an increased flow rate (as a result of the exercise ).
The projected aortic valve area at a normal flow rate can also be calculated. Low-dose dobutamine stress echocardiography (starting at 2.5 μg/kg/min up to a maximum of 20 μg/kg/min) can also be considered in symptomatic patients, but caution is needed, with close monitoring of blood pressure and LVOT velocity. Dobutamine stress echocardiography should not be used in patients with severe LV restrictive physiology.
If the patient is symptomatic and the AS is severe, then aortic valve replacement is indicated, either via a surgical or transcatheter procedure. If stress echo findings and/or a low MDCT aortic valvular calcium score indicate that AS is pseudo-severe (not true-severe) then aortic valve replacement is not indicated, but the patient will need a regular follow-up.
For low flow -low gradient aortic stenosis I recommend this VIDEO with cases (from you tube channel Cardiology Database , by dr Salvatore Costa)
LINK https://www.youtube.com/watch?v=m8NkicX6IM8
Useful links and bibliography
Baumgarther H, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease: The Task Force for the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS), European Heart Journal, , ehx391, https://doi.org/10.1093/eurheartj/ehx391
LINK https://academic.oup.com/eurheartj/article/4095039/2017-ESC-EACTS-Guidelines-for-the-management-of#supplementary-data
2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease
ESC Guidelines on the management of valvular heart disease (version 2012)
Nishimura, et al. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease
LINK2017 AHA/ACC Focused Update- Valvular Heart Disease
Baumgartner H, Hung J, Bermejo J, et al.: Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice, Eur J Echocardiogr 2009;10:1–25
LINK:
https://www.escardio.org/static_file/Escardio/Subspecialty/EACVI/position-papers/EAE-recommendations-valve-stenosis.pdf
Pibarot P, Dumesnil JG. Low-flow, low-gradient aortic stenosis with normal and depressed left ventricular ejection fraction. J Am Coll Cardiol. 2012;60:1845-53. | {
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-5,424,458,054,026,376,000 | Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds.Sulfur Compounds: Inorganic or organic compounds that contain sulfur as an integral part of the molecule.Volatile Organic Compounds: Organic compounds that have a relatively high VAPOR PRESSURE at room temperature.Structure-Activity Relationship: The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.Plant Extracts: Concentrated pharmaceutical preparations of plants obtained by removing active constituents with a suitable solvent, which is evaporated away, and adjusting the residue to a prescribed standard.Drug Evaluation, Preclinical: Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications.Magnetic Resonance Spectroscopy: Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (MAGNETIC RESONANCE IMAGING).Phenols: Benzene derivatives that include one or more hydroxyl groups attached to the ring structure.Heterocyclic Compounds: Ring compounds having atoms other than carbon in their nuclei. (Grant & Hackh's Chemical Dictionary, 5th ed)Inhibitory Concentration 50: The concentration of a compound needed to reduce population growth of organisms, including eukaryotic cells, by 50% in vitro. Though often expressed to denote in vitro antibacterial activity, it is also used as a benchmark for cytotoxicity to eukaryotic cells in culture.Biphenyl CompoundsSulfhydryl Compounds: Compounds containing the -SH radical.Small Molecule Libraries: Large collections of small molecules (molecular weight about 600 or less), of similar or diverse nature which are used for high-throughput screening analysis of the gene function, protein interaction, cellular processing, biochemical pathways, or other chemical interactions.Organotin Compounds: Organic compounds which contain tin in the molecule. Used widely in industry and agriculture.Aniline CompoundsSpiro Compounds: A group of compounds consisting in part of two rings sharing one atom (usually a carbon) in common.Nitrogen Compounds: Inorganic compounds that contain nitrogen as an integral part of the molecule.Chromatography, High Pressure Liquid: Liquid chromatographic techniques which feature high inlet pressures, high sensitivity, and high speed.Stereoisomerism: The phenomenon whereby compounds whose molecules have the same number and kind of atoms and the same atomic arrangement, but differ in their spatial relationships. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed)Drug Design: The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis.Dose-Response Relationship, Drug: The relationship between the dose of an administered drug and the response of the organism to the drug.Nitroso CompoundsOrganometallic Compounds: A class of compounds of the type R-M, where a C atom is joined directly to any other element except H, C, N, O, F, Cl, Br, I, or At. (Grant & Hackh's Chemical Dictionary, 5th ed)Organoselenium Compounds: Organic compounds which contain selenium as an integral part of the molecule.Drug Screening Assays, Antitumor: Methods of investigating the effectiveness of anticancer cytotoxic drugs and biologic inhibitors. These include in vitro cell-kill models and cytostatic dye exclusion tests as well as in vivo measurement of tumor growth parameters in laboratory animals.Organophosphorus Compounds: Organic compounds that contain phosphorus as an integral part of the molecule. Included under this heading is broad array of synthetic compounds that are used as PESTICIDES and DRUGS.Azo CompoundsGas Chromatography-Mass Spectrometry: A microanalytical technique combining mass spectrometry and gas chromatography for the qualitative as well as quantitative determinations of compounds.Kinetics: The rate dynamics in chemical or physical systems.Epoxy Compounds: Organic compounds that include a cyclic ether with three ring atoms in their structure. They are commonly used as precursors for POLYMERS such as EPOXY RESINS.Volatilization: A phase transition from liquid state to gas state, which is affected by Raoult's law. It can be accomplished by fractional distillation.High-Throughput Screening Assays: Rapid methods of measuring the effects of an agent in a biological or chemical assay. The assay usually involves some form of automation or a way to conduct multiple assays at the same time using sample arrays.Quaternary Ammonium Compounds: Derivatives of ammonium compounds, NH4+ Y-, in which all four of the hydrogens bonded to nitrogen have been replaced with hydrocarbyl groups. These are distinguished from IMINES which are RN=CR2.Drug Discovery: The process of finding chemicals for potential therapeutic use.Polycyclic Compounds: Compounds consisting of two or more fused ring structures.p-Methoxy-N-methylphenethylamine: A potent mast cell degranulator. It is involved in histamine release.Hydrocarbons, Aromatic: Organic compounds containing carbon and hydrogen in the form of an unsaturated, usually hexagonal ring structure. The compounds can be single ring, or double, triple, or multiple fused rings.Antineoplastic Agents: Substances that inhibit or prevent the proliferation of NEOPLASMS.Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.Mass Spectrometry: An analytical method used in determining the identity of a chemical based on its mass using mass analyzers/mass spectrometers.Benzyl CompoundsOrganic Chemicals: A broad class of substances containing carbon and its derivatives. Many of these chemicals will frequently contain hydrogen with or without oxygen, nitrogen, sulfur, phosphorus, and other elements. They exist in either carbon chain or carbon ring form.Terphenyl Compounds: Compounds consisting of benzene rings linked to each other in either ortho, meta or para positions. Permitted are any substitutions, but ring fusion to any of the benzene rings is not allowed.Cell Line, Tumor: A cell line derived from cultured tumor cells.TriterpenesFurans: Compounds with a 5-membered ring of four carbons and an oxygen. They are aromatic heterocycles. The reduced form is tetrahydrofuran.Oxidation-Reduction: A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471).Molecular Conformation: The characteristic three-dimensional shape of a molecule.Allyl CompoundsModels, Molecular: Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.Spectrophotometry, Ultraviolet: Determination of the spectra of ultraviolet absorption by specific molecules in gases or liquids, for example Cl2, SO2, NO2, CS2, ozone, mercury vapor, and various unsaturated compounds. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)Glycosides: Any compound that contains a constituent sugar, in which the hydroxyl group attached to the first carbon is substituted by an alcoholic, phenolic, or other group. They are named specifically for the sugar contained, such as glucoside (glucose), pentoside (pentose), fructoside (fructose), etc. Upon hydrolysis, a sugar and nonsugar component (aglycone) are formed. (From Dorland, 28th ed; From Miall's Dictionary of Chemistry, 5th ed)Heterocyclic Compounds, 2-Ring: A class of organic compounds containing two ring structures, one of which is made up of more than one kind of atom, usually carbon plus another atom. The heterocycle may be either aromatic or nonaromatic.PicratesSpectrophotometry, Infrared: Spectrophotometry in the infrared region, usually for the purpose of chemical analysis through measurement of absorption spectra associated with rotational and vibrational energy levels of molecules. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)Selenium Compounds: Inorganic compounds that contain selenium as an integral part of the molecule.Plant Bark: The outer layer of the woody parts of plants.Plants, Medicinal: Plants whose roots, leaves, seeds, bark, or other constituent parts possess therapeutic, tonic, purgative, curative or other pharmacologic attributes, when administered to man or animals.Anti-Bacterial Agents: Substances that reduce the growth or reproduction of BACTERIA.Quantitative Structure-Activity Relationship: A quantitative prediction of the biological, ecotoxicological or pharmaceutical activity of a molecule. It is based upon structure and activity information gathered from a series of similar compounds.Indicators and Reagents: Substances used for the detection, identification, analysis, etc. of chemical, biological, or pathologic processes or conditions. Indicators are substances that change in physical appearance, e.g., color, at or approaching the endpoint of a chemical titration, e.g., on the passage between acidity and alkalinity. Reagents are substances used for the detection or determination of another substance by chemical or microscopical means, especially analysis. Types of reagents are precipitants, solvents, oxidizers, reducers, fluxes, and colorimetric reagents. (From Grant & Hackh's Chemical Dictionary, 5th ed, p301, p499)Biotransformation: The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alterations may be divided into METABOLIC DETOXICATION, PHASE I and METABOLIC DETOXICATION, PHASE II.Trialkyltin Compounds: Organometallic compounds which contain tin and three alkyl groups.Molecular Sequence Data: Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Plant Components, Aerial: The above-ground plant without the roots.Flavonoids: A group of phenyl benzopyrans named for having structures like FLAVONES.Bicyclo CompoundsBiodegradation, Environmental: Elimination of ENVIRONMENTAL POLLUTANTS; PESTICIDES and other waste using living organisms, usually involving intervention of environmental or sanitation engineers.Chromatography, Thin Layer: Chromatography on thin layers of adsorbents rather than in columns. The adsorbent can be alumina, silica gel, silicates, charcoals, or cellulose. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)Microbial Sensitivity Tests: Any tests that demonstrate the relative efficacy of different chemotherapeutic agents against specific microorganisms (i.e., bacteria, fungi, viruses).SesquiterpenesDiterpenes: Twenty-carbon compounds derived from MEVALONIC ACID or deoxyxylulose phosphate.Biological Products: Complex pharmaceutical substances, preparations, or matter derived from organisms usually obtained by biological methods or assay.Terpenes: A class of compounds composed of repeating 5-carbon units of HEMITERPENES.Bridged Compounds: Cyclic hydrocarbons that contain multiple rings and share one or more atoms.Heterocyclic Compounds with 4 or More Rings: A class of organic compounds containing four or more ring structures, one of which is made up of more than one kind of atom, usually carbon plus another atom. The heterocycle may be either aromatic or nonaromatic.KetonesCell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability.Chemistry: A basic science concerned with the composition, structure, and properties of matter; and the reactions that occur between substances and the associated energy exchange.Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form.Combinatorial Chemistry Techniques: A technology, in which sets of reactions for solution or solid-phase synthesis, is used to create molecular libraries for analysis of compounds on a large scale.ThiazolesHydrogen-Ion Concentration: The normality of a solution with respect to HYDROGEN ions; H+. It is related to acidity measurements in most cases by pH = log 1/2[1/(H+)], where (H+) is the hydrogen ion concentration in gram equivalents per liter of solution. (McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed)Bacteria: One of the three domains of life (the others being Eukarya and ARCHAEA), also called Eubacteria. They are unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. Bacteria can be classified by their response to OXYGEN: aerobic, anaerobic, or facultatively anaerobic; by the mode by which they obtain their energy: chemotrophy (via chemical reaction) or PHOTOTROPHY (via light reaction); for chemotrophs by their source of chemical energy: CHEMOLITHOTROPHY (from inorganic compounds) or chemoorganotrophy (from organic compounds); and by their source for CARBON; NITROGEN; etc.; HETEROTROPHY (from organic sources) or AUTOTROPHY (from CARBON DIOXIDE). They can also be classified by whether or not they stain (based on the structure of their CELL WALLS) with CRYSTAL VIOLET dye: gram-negative or gram-positive.Antioxidants: Naturally occurring or synthetic substances that inhibit or retard the oxidation of a substance to which it is added. They counteract the harmful and damaging effects of oxidation in animal tissues.Chemical Phenomena: The composition, conformation, and properties of atoms and molecules, and their reaction and interaction processes.Indoles: Benzopyrroles with the nitrogen at the number one carbon adjacent to the benzyl portion, in contrast to ISOINDOLES which have the nitrogen away from the six-membered ring.GlucosidesBenzofurans: Compounds that contain a BENZENE ring fused to a furan ring.Benzene DerivativesSpectrometry, Mass, Electrospray Ionization: A mass spectrometry technique used for analysis of nonvolatile compounds such as proteins and macromolecules. The technique involves preparing electrically charged droplets from analyte molecules dissolved in solvent. The electrically charged droplets enter a vacuum chamber where the solvent is evaporated. Evaporation of solvent reduces the droplet size, thereby increasing the coulombic repulsion within the droplet. As the charged droplets get smaller, the excess charge within them causes them to disintegrate and release analyte molecules. The volatilized analyte molecules are then analyzed by mass spectrometry.Binding Sites: The parts of a macromolecule that directly participate in its specific combination with another molecule.Monoterpenes: Compounds with a core of 10 carbons generally formed via the mevalonate pathway from the combination of 3,3-dimethylallyl pyrophosphate and isopentenyl pyrophosphate. They are cyclized and oxidized in a variety of ways. Due to the low molecular weight many of them exist in the form of essential oils (OILS, VOLATILE).Gold Compounds: Inorganic compounds that contain gold as an integral part of the molecule.Ligands: A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed)Mutation: Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.Ferrous Compounds: Inorganic or organic compounds that contain divalent iron.Plant Leaves: Expanded structures, usually green, of vascular plants, characteristically consisting of a bladelike expansion attached to a stem, and functioning as the principal organ of photosynthesis and transpiration. (American Heritage Dictionary, 2d ed)Models, Chemical: Theoretical representations that simulate the behavior or activity of chemical processes or phenomena; includes the use of mathematical equations, computers, and other electronic equipment.Benzhydryl Compounds: Compounds which contain the methyl radical substituted with two benzene rings. Permitted are any substituents, but ring fusion to any of the benzene rings is not allowed.Chromatography, Gas: Fractionation of a vaporized sample as a consequence of partition between a mobile gaseous phase and a stationary phase held in a column. Two types are gas-solid chromatography, where the fixed phase is a solid, and gas-liquid, in which the stationary phase is a nonvolatile liquid supported on an inert solid matrix.Cells, Cultured: Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.Coumarins: Synthetic or naturally occurring substances related to coumarin, the delta-lactone of coumarinic acid.Amines: A group of compounds derived from ammonia by substituting organic radicals for the hydrogens. (From Grant & Hackh's Chemical Dictionary, 5th ed)Time Factors: Elements of limited time intervals, contributing to particular results or situations.Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.Ruthenium Compounds: Inorganic compounds that contain ruthenium as an integral part of the molecule.Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts.Carboxylic Acids: Organic compounds containing the carboxy group (-COOH). This group of compounds includes amino acids and fatty acids. Carboxylic acids can be saturated, unsaturated, or aromatic.Drugs, Chinese Herbal: Chinese herbal or plant extracts which are used as drugs to treat diseases or promote general well-being. The concept does not include synthesized compounds manufactured in China.Hydrocarbons, HalogenatedFungi: A kingdom of eukaryotic, heterotrophic organisms that live parasitically as saprobes, including MUSHROOMS; YEASTS; smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi, commonly known as molds, refer to those that grow as multicellular colonies.EthersBiological Assay: A method of measuring the effects of a biologically active substance using an intermediate in vivo or in vitro tissue or cell model under controlled conditions. It includes virulence studies in animal fetuses in utero, mouse convulsion bioassay of insulin, quantitation of tumor-initiator systems in mouse skin, calculation of potentiating effects of a hormonal factor in an isolated strip of contracting stomach muscle, etc.Antiviral Agents: Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly.Boron Compounds: Inorganic or organic compounds that contain boron as an integral part of the molecule.Spectrometry, Mass, Fast Atom Bombardment: A mass spectrometric technique that is used for the analysis of a wide range of biomolecules, such as glycoalkaloids, glycoproteins, polysaccharides, and peptides. Positive and negative fast atom bombardment spectra are recorded on a mass spectrometer fitted with an atom gun with xenon as the customary beam. The mass spectra obtained contain molecular weight recognition as well as sequence information.Benzylidene Compounds: Compounds containing the PhCH= radical.Vanadium Compounds: Inorganic compounds that contain vanadium as an integral part of the molecule.Hydroxybenzoates: Benzoate derivatives substituted by one or more hydroxy groups in any position on the benzene ring.Oils, Volatile: Oils which evaporate readily. The volatile oils occur in aromatic plants, to which they give odor and other characteristics. Most volatile oils consist of a mixture of two or more TERPENES or of a mixture of an eleoptene (the more volatile constituent of a volatile oil) with a stearopten (the more solid constituent). The synonym essential oils refers to the essence of a plant, as its perfume or scent, and not to its indispensability.Rats, Sprague-Dawley: A strain of albino rat used widely for experimental purposes because of its calmness and ease of handling. It was developed by the Sprague-Dawley Animal Company.EstersSulfonium Compounds: Sulfur compounds in which the sulfur atom is attached to three organic radicals and an electronegative element or radical.Ferric Compounds: Inorganic or organic compounds containing trivalent iron.Benzoates: Derivatives of BENZOIC ACID. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the carboxybenzene structure.Heterocyclic Compounds, 3-Ring: A class of organic compounds containing three ring structures, one of which is made up of more than one kind of atom, usually carbon plus another atom. The heterocycle may be either aromatic or nonaromaticCatechols: A group of 1,2-benzenediols that contain the general formula R-C6H5O2.Organothiophosphorus Compounds: Compounds containing carbon-phosphorus bonds in which the phosphorus component is also bonded to one or more sulfur atoms. Many of these compounds function as CHOLINERGIC AGENTS and as INSECTICIDES.Antifungal Agents: Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from FUNGICIDES, INDUSTRIAL because they defend against fungi present in human or animal tissues.Hydrocarbons, Chlorinated: Hydrocarbon compounds with one or more of the hydrogens replaced by CHLORINE.Liver: A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances.Hydrocarbons, FluorinatedPyridinium CompoundsMethanol: A colorless, flammable liquid used in the manufacture of FORMALDEHYDE and ACETIC ACID, in chemical synthesis, antifreeze, and as a solvent. Ingestion of methanol is toxic and may cause blindness.HydrocarbonsPolyphenols: A large class of organic compounds having more than one PHENOL group.Lactones: Cyclic esters of hydroxy carboxylic acids, containing a 1-oxacycloalkan-2-one structure. Large cyclic lactones of over a dozen atoms are MACROLIDES.Sulfides: Chemical groups containing the covalent sulfur bonds -S-. The sulfur atom can be bound to inorganic or organic moieties.Compound Eye, Arthropod: Light sensory organ in ARTHROPODS consisting of a large number of ommatidia, each functioning as an independent photoreceptor unit.Molecular Docking Simulation: A computer simulation technique that is used to model the interaction between two molecules. Typically the docking simulation measures the interactions of a small molecule or ligand with a part of a larger molecule such as a protein.Free Radical Scavengers: Substances that influence the course of a chemical reaction by ready combination with free radicals. Among other effects, this combining activity protects pancreatic islets against damage by cytokines and prevents myocardial and pulmonary perfusion injuries.CinnamatesPyransPyridines: Compounds with a six membered aromatic ring containing NITROGEN. The saturated version is PIPERIDINES.Rats, Wistar: A strain of albino rat developed at the Wistar Institute that has spread widely at other institutions. This has markedly diluted the original strain.Vinyl CompoundsSulfonic Acids: Inorganic or organic oxy acids of sulfur which contain the RSO2(OH) radical.Crystallography, X-Ray: The study of crystal structure using X-RAY DIFFRACTION techniques. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)Escherichia coli: A species of gram-negative, facultatively anaerobic, rod-shaped bacteria (GRAM-NEGATIVE FACULTATIVELY ANAEROBIC RODS) commonly found in the lower part of the intestine of warm-blooded animals. It is usually nonpathogenic, but some strains are known to produce DIARRHEA and pyogenic infections. Pathogenic strains (virotypes) are classified by their specific pathogenic mechanisms such as toxins (ENTEROTOXIGENIC ESCHERICHIA COLI), etc.Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.Alcohols: Alkyl compounds containing a hydroxyl group. They are classified according to relation of the carbon atom: primary alcohols, R-CH2OH; secondary alcohols, R2-CHOH; tertiary alcohols, R3-COH. (From Grant & Hackh's Chemical Dictionary, 5th ed)Parasitic Sensitivity Tests: Tests that demonstrate the relative effectiveness of chemotherapeutic agents against specific parasites.Antiprotozoal Agents: Substances that are destructive to protozoans.Aldehydes: Organic compounds containing a carbonyl group in the form -CHO.Fermentation: Anaerobic degradation of GLUCOSE or other organic nutrients to gain energy in the form of ATP. End products vary depending on organisms, substrates, and enzymatic pathways. Common fermentation products include ETHANOL and LACTIC ACID.Acetates: Derivatives of ACETIC ACID. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the carboxymethane structure.Apoptosis: One of the mechanisms by which CELL DEATH occurs (compare with NECROSIS and AUTOPHAGOCYTOSIS). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA; (DNA FRAGMENTATION); at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth.Alkaloids: Organic nitrogenous bases. Many alkaloids of medical importance occur in the animal and vegetable kingdoms, and some have been synthesized. (Grant & Hackh's Chemical Dictionary, 5th ed)Solvents: Liquids that dissolve other substances (solutes), generally solids, without any change in chemical composition, as, water containing sugar. (Grant & Hackh's Chemical Dictionary, 5th ed)Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes.Stilbenes: Organic compounds that contain 1,2-diphenylethylene as a functional group.Porifera: The phylum of sponges which are sessile, suspension-feeding, multicellular animals that utilize flagellated cells called choanocytes to circulate water. Most are hermaphroditic. They are probably an early evolutionary side branch that gave rise to no other group of animals. Except for about 150 freshwater species, sponges are marine animals. They are a source of ALKALOIDS; STEROLS; and other complex molecules useful in medicine and biological research.Trypanocidal Agents: Agents destructive to the protozoal organisms belonging to the suborder TRYPANOSOMATINA.Imidazoles: Compounds containing 1,3-diazole, a five membered aromatic ring containing two nitrogen atoms separated by one of the carbons. Chemically reduced ones include IMIDAZOLINES and IMIDAZOLIDINES. Distinguish from 1,2-diazole (PYRAZOLES).Chalcones: Compounds based on CHALCONE. They are important intermediates in the formation of FLAVONOIDS.QuinolinesSpectrophotometry: The art or process of comparing photometrically the relative intensities of the light in different parts of the spectrum.Naphthoquinones: Naphthalene rings which contain two ketone moieties in any position. They can be substituted in any position except at the ketone groups.Mutagenicity Tests: Tests of chemical substances and physical agents for mutagenic potential. They include microbial, insect, mammalian cell, and whole animal tests.Plant Roots: The usually underground portions of a plant that serve as support, store food, and through which water and mineral nutrients enter the plant. (From American Heritage Dictionary, 1982; Concise Dictionary of Biology, 1990)Chlorogenic Acid: A naturally occurring phenolic acid which is a carcinogenic inhibitor. It has also been shown to prevent paraquat-induced oxidative stress in rats. (From J Chromatogr A 1996;741(2):223-31; Biosci Biotechnol Biochem 1996;60(5):765-68).Xenobiotics: Chemical substances that are foreign to the biological system. They include naturally occurring compounds, drugs, environmental agents, carcinogens, insecticides, etc.Platinum Compounds: Inorganic compounds which contain platinum as the central atom.Binding, Competitive: The interaction of two or more substrates or ligands with the same binding site. The displacement of one by the other is used in quantitative and selective affinity measurements.Organosilicon Compounds: Organic compounds that contain silicon as an integral part of the molecule.Mercury Compounds: Inorganic compounds that contain mercury as an integral part of the molecule.Spectrum Analysis: The measurement of the amplitude of the components of a complex waveform throughout the frequency range of the waveform. (McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed)Flavones: A group of 4-keto-FLAVONOIDS.Cell Proliferation: All of the processes involved in increasing CELL NUMBER including CELL DIVISION.Organogold Compounds: Organic compounds that contain GOLD as an integral part of the molecule. Some are used as ANTIRHEUMATIC AGENTS. The term chrysotherapy derives from an ancient Greek term for gold.BenzaldehydesStreptomyces: A genus of bacteria that form a nonfragmented aerial mycelium. Many species have been identified with some being pathogenic. This genus is responsible for producing a majority of the ANTI-BACTERIAL AGENTS of practical value.Bicyclo Compounds, Heterocyclic: A class of saturated compounds consisting of two rings only, having two or more atoms in common, containing at least one hetero atom, and that take the name of an open chain hydrocarbon containing the same total number of atoms. (From Riguady et al., Nomenclature of Organic Chemistry, 1979, p31)Anthraquinones: Compounds based on ANTHRACENES which contain two KETONES in any position. Substitutions can be in any position except on the ketone groups.Environmental Pollutants: Substances or energies, for example heat or light, which when introduced into the air, water, or land threaten life or health of individuals or ECOSYSTEMS.Lethal Dose 50: The dose amount of poisonous or toxic substance or dose of ionizing radiation required to kill 50% of the tested population.PeroxidasesPhenol: An antiseptic and disinfectant aromatic alcohol.Rhizome: Root-like underground horizontal stem of plants that produces shoots above and roots below. Distinguished from true roots which don't have buds and nodes. Similar to true roots in being underground and thickened by storage deposits.Phytotherapy: Use of plants or herbs to treat diseases or to alleviate pain.Toxicity Tests: An array of tests used to determine the toxicity of a substance to living systems. These include tests on clinical drugs, foods, and environmental pollutants.Water Pollutants, Chemical: Chemical compounds which pollute the water of rivers, streams, lakes, the sea, reservoirs, or other bodies of water.Anti-Infective Agents: Substances that prevent infectious agents or organisms from spreading or kill infectious agents in order to prevent the spread of infection.Pyrazoles: Azoles of two nitrogens at the 1,2 positions, next to each other, in contrast with IMIDAZOLES in which they are at the 1,3 positions.Antineoplastic Agents, Phytogenic: Agents obtained from higher plants that have demonstrable cytostatic or antineoplastic activity.Carcinogens: Substances that increase the risk of NEOPLASMS in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included.Alkanes: The generic name for the group of aliphatic hydrocarbons Cn-H2n+2. They are denoted by the suffix -ane. (Grant & Hackh's Chemical Dictionary, 5th ed)Cricetinae: A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.Calcium Compounds: Inorganic compounds that contain calcium as an integral part of the molecule.
Influence of a new antiulcer agent, ammonium 7-oxobicyclo (2, 2, 1) hept-5-ene-3-carbamoyl-2-carboxylate (KF-392) on gastric lesions and gastric mucosal barrier in rats. (1/528)
Antiulcer effects of KF-392 were studied in several experimental gastric ulcer models in rats. It was found that KF-392 given orally at 1.0 to 5.0 mg/kg had a marked suppression on the developments of Shay ulcer as well as the aspirin-, stress-, and reserpine-induced gastric lesions. The influence of KF-392 on gastric mucosal barrier was also studied. A back diffusion of H+ into the gastric mucosa and a fall of transmucosal potential difference were induced with KF-392 given orally at the above mentioned doses. KF-392 given s.c. at 5.0 mg/kg showed no inhibition of Shay ulcer and no induction of back diffusion of H+ into the gastric mucosa. (+info)
BE-31405, a new antifungal antibiotic produced by Penicillium minioluteum. I. Description of producing organism, fermentation, isolation, physico-chemical and biological properties. (2/528)
A new antifungal antibiotic, BE-31405, was isolated from the culture broth of a fungal strain, Penicillium minioluteum F31405. BE-31405 was isolated by adsorption on high porous polymer resin (Diaion HP-20), followed by solvent extraction, precipitation and crystallization. BE-31405 showed potent growth inhibitory activity against pathogenic fungal strains such as Candida albicans, Candida glabrata and Cryptococcus neoformans, but did not show cytotoxic activity against mammalian cells such as P388 mouse leukemia. The mechanism studies indicated that BE-31405 inhibited the protein synthesis of C. albicans but not of mammalian cells. (+info)
A phosphatidylcholine-specific phospholipase C regulates activation of p42/44 mitogen-activated protein kinases in lipopolysaccharide-stimulated human alveolar macrophages. (3/528)
This study uses human alveolar macrophages to determine whether activation of a phosphatidylcholine (PC)-specific phospholipase C (PC-PLC) is linked to activation of the p42/44 (ERK) kinases by LPS. LPS-induced ERK kinase activation was inhibited by tricyclodecan-9-yl xanthogenate (D609), a relatively specific inhibitor of PC-PLC. LPS also increased amounts of diacylglycerol (DAG), and this increase in DAG was inhibited by D609. LPS induction of DAG was, at least in part, derived from PC hydrolysis. Ceramide was also increased in LPS-treated alveolar macrophages, and this increase in ceramide was inhibited by D609. Addition of exogenous C2 ceramide or bacterial-derived sphingomyelinase to alveolar macrophages increased ERK kinase activity. LPS also activated PKC zeta, and this activation was inhibited by D609. LPS-activated PKC zeta phosphorylated MAP kinase kinase, the kinase directly upstream of the ERK kinases. LPS-induced cytokine production (RNA and protein) was also inhibited by D609. As an aggregate, these studies support the hypothesis that one way by which LPS activates the ERK kinases is via activation of PC-PLC and that activation of a PC-PLC is an important component of macrophage activation by LPS. (+info)
In vitro endothelial differentiation of long-term cultured murine embryonic yolk sac cells induced by matrigel. (4/528)
The yolk sac of an early mammalian embryo contains progenitors of hematopoietic cells and vascular endothelial cells. We established a cell line, YS4, from murine embryonic yolk sac 10 years ago. The line has been successfully cultured since then. To determine whether these long-term cultured yolk sac cells still have the potential to differentiate into endothelial cells, an in vitro model of yolk sac cell differentiation into tubeforming endothelial cells was established in the present study by culturing the yolk sac cells on basement membrane proteins (Matrigel). The results indicate that upon plating onto Matrigel, YS4 cells attach quickly, align in tandem, and form a complete network of capillary structures within 12 h. By using antibodies against the known components of Matrigel in a tube formation inhibition assay, we found that extracellular matrix proteins such as laminin, collagen IV, vitronectin, and fibronectin are the most important components in the Matrigel which induce the yolk sac cells to undergo endothelial differentiation. New basement membrane proteins are also required for the endothelial differentiation process, as indicated by the fact that base membrane protein synthesis inhibitor, D609, can block the differentiation process. Furthermore, our experiments revealed the involvement of several signal transduction pathways, such as protein kinase A, C and protein tyrosine kinase in this differentiation process. (+info)
Analysis of the behaviour of selected CCKB/gastrin receptor antagonists in radioligand binding assays performed in mouse and rat cerebral cortex. (5/528)
1. The previously described complex behaviour of the CCKB/gastrin receptor antagonist, L-365,260, in radioligand binding assays could be explained by a variable population of two binding sites. We have investigated whether other CCKB/gastrin receptor ligands (PD134,308, PD140,376, YM022 and JB93182) can distinguish between these sites. 2. In the mouse cortex assay, Hill slopes were not different from unity and the ligand pKI values did not differ when either [125I]-BH-CCK-8S or [3H]-PD140,376 was used as label as expected for a single site (G2). 3. In the rat cortex, where previous analysis of replicate (n=48) L-365,260 data indicated the presence of two CCKB/gastrin sites (G1 and G2), the competition data for PD134,308, PD140,376, YM022 and JB93182 could be explained by a homogeneous population of CCKB/gastrin sites because the Hill slope estimates were not significantly different from unity. However, the estimated affinity values for JB93182 and YM022 were significantly higher and that for PD134,308 was significantly lower than those obtained in the mouse cortex when the same radioligand was used. In view of our previous data obtained with L-365,260, the rat cortex data were also interpreted using a two-site model. In this analysis, SR27897 expressed approximately 9 fold, PD134,308 approximately 13 fold and PD140,376 approximately 11 fold selectivity for the G2 site. In contrast, JB93182 expressed approximately 23 fold and YM022 approximately 4 fold selectivity for the G1 site. If the two-site interpretation of the data is valid then, because of its reverse selectivity to L-365,260, JB93182 has been identified as a compound which if radiolabelled could provide a test of this receptor subdivision. (+info)
Characterization of the binding of a novel radioligand to CCKB/gastrin receptors in membranes from rat cerebral cortex. (6/528)
1. We have investigated the binding of a novel radiolabelled CCKB/gastrin receptor ligand, [3H]-JB93182 (5[[[(1S)-[[(3,5-dicarboxyphenyl)amino]carbonyl]-2-phenylethyla mino]-carbonyl]-6-[[(1-adamantylmethyl) amino]carbonyl]-indole), to sites in rat cortex membranes. 2. The [3H]-JB93182 was 97% radiochemically pure as assessed by reverse-phase HPLC (RP-HPLC) and was not degraded by incubation (150 min) with rat cortex membranes. 3. Saturation analysis indicated that [3H]-JB93182 labelled a homogeneous population of receptors in rat cortex membranes (pKD=9.48+/-0.08, Bmax=3.61+/-0.65 pmol g(-1) tissue, nH=0.97+/-0.02, n=5). The pKD was not significantly different when estimated by association-dissociation analysis (pKD=9.73+/-0.11; n=10). 4. In competition studies, the low affinity of the CCKA receptor antagonists, L-364,718; SR27897 and 2-NAP, suggest that, under the assay conditions employed, [3H]-JB93182 (0.3 nM) does not label CCKA receptors in the rat cortex. 5. The affinity estimates obtained for reference CCKB/gastrin receptor antagonists were indistinguishable from one of the affinity values obtained when a two site model was used to interpret [125I]-BH-CCK8S competition curves obtained in the same tissue (Harper et al., 1999). 6. This study provides further evidence for the existence of two CCKB/gastrin sites in rat cortex. [3H]-JB93182 appears to label selectively sites previously designated as gastrin-G1 and therefore it may be a useful compound for the further discrimination and characterization of these putative receptor subtypes. (+info)
Nuclei contain two differentially regulated pools of diacylglycerol. (7/528)
A number of recent studies have highlighted the presence of a nuclear pool of inositol lipids [1] [2] that is regulated during progression through the cell cycle [1] [3], differentiation [1] [2] and after DNA damage [2], suggesting that a number of different regulatory pathways impinge upon this pool of lipids. It has been suggested that the downstream consequence of the activation of one of these nuclear phosphoinositide (PI) regulatory pathways is the generation of nuclear diacylglycerol (DAG) [1] [3] [4], which is important in the activation of nuclear protein kinase C (PKC) [5] [6] [7]. Activation of PKC in turn appears to regulate the progression of cells through G1 and into S phase [4] and through G2 to mitosis [3] [8] [9] [10] [11]. Although the evidence is enticing, there is as yet no direct demonstration that nuclear PIs can be hydrolysed to generate nuclear DAG. Previous data in murine erythroleukemia (MEL) cells have suggested that nuclear phosphoinositidase Cbeta1 (PIC-beta1) activity is important in the generation of nuclear DAG. Here, we demonstrate that the molecular species of nuclear DAG bears little resemblance to the PI pool and is unlikely to be generated directly by hydrolysis of these inositol lipids. Further, we show that there are in fact two distinct subnuclear pools of DAG; one that is highly disaturated and mono-unsaturated (representing more than 90% of the total nuclear DAG) and one that is highly polyunsaturated and is likely to be derived from the hydrolysis of PI. Analysis of these pools, either after differentiation or during cell-cycle progression, suggests that the pools are independently regulated, possibly by the regulation of two different nuclear phospholipase Cs (PLCs). (+info)
DNA damage increases sensitivity to vinca alkaloids and decreases sensitivity to taxanes through p53-dependent repression of microtubule-associated protein 4. (8/528)
Taxanes and Vinca alkaloids are among the most active classes of drugs in the treatment of cancer. Yet, fewer than 50% of previously untreated patients respond, and clinicians have few ways of predicting who will benefit from treatment and who will not. Mutations in p53 occur in more than half of human malignancies and may alter the sensitivity to a variety of anticancer therapies. We have shown that the transcriptional status of p53 determines the sensitivity to antimicrotubule drugs and that this is mediated through the regulation of microtubule-associated protein 4 (MAP4). Expression of MAP4 is transcriptionally repressed by wild-type p53. Increased expression of MAP4, which occurs when p53 is transcriptionally inactive, increases microtubule polymerization, paclitaxel binding, and sensitivity to paclitaxel, a drug that stabilizes polymerized microtubules. In contrast, overexpression of MAP4 decreases microtubule binding and sensitivity to Vinca alkaloids, which promotes microtubule depolymerization. To determine whether induction of endogenous wild-type p53 by DNA-damaging agents alters the expression of MAP4 and changes the sensitivity to antimicrotubule drugs, we assayed cell lines with wild-type or mutant p53 for the expression of MAP4 and drug sensitivity before and after DNA damage. UV irradiation, bleomycin, and doxorubicin increased wild-type p53 expression and decreased MAP4 expression. These changes were associated with decreased sensitivity to paclitaxel and increased sensitivity to vinblastine. These changes in drug sensitivity were no longer observed when p53 and MAP4 returned to baseline levels. Changes in drug sensitivity following DNA-damaging agents were associated with decreased binding of paclitaxel and increased binding of Vinca alkaloids. In contrast, DNA damage did not alter the sensitivity to non-microtubule-active drugs, such as 1-beta-D-arabinofuranosylcytosine and doxorubicin. Changes in drug sensitivity following DNA-damaging drugs were not observed in cells with mutant p53. These studies demonstrate that induction of wild-type p53 by DNA-damaging agents can affect the sensitivity to antimicrotubule drugs through the regulation of MAP4 expression and may have implications for the design of clinical anticancer therapies. (+info)
• The aminolysis of a number of acyclic and cyclic compounds containing P-NR-P or P-CH2-P skeletons have been studied. (gla.ac.uk)
• In 2017, the lab of Marinella Mazzanti at EPFL was able to convert molecular nitrogen into ammonia in ambient conditions by synthesizing a compound containing two uranium(III) ions and three potassium centers held together by a nitride group. (eurekalert.org)
• In particular, the collagen cross-linking is achieved by a Laccase-induced peptide cross-linking and suitable bridge molecules. (google.co.uk)
• Essentially substituted dihydroxyarmotes and/or substrates of the lignolytic polyphenoloxidases, such as Laccases, are suitable as bridge molecules. (google.co.uk)
• The acid catalysed dehydration either turns the bridge into a double bond (ozonolysis of this product yields 2 molecules of cyclopentanone) or else turns a neighbouring bond into a double bond (ozonolysis of this one yields a molecule with an aldehyde at one end of the chain, a ketone in the middle and a cyclopentane ring at the other end of the chain). (physicsforums.com)
• Wastes from fruits and vegetable processing are shown to contained valuable molecules (antioxidants, dietary fibers, proteins, natural colorants, aroma compounds, etc.) which can be extracted, purified and valorized in value-added products. (intechopen.com)
• 1996 , 118(24) , 5826-5827 (Dimolybdenum Compounds with Crosswise-Bridging Acetonitrile Molecules). (tum.de)
• 5. The intermetallic compounds of claim 1, further reacted with a halide activator selected from the group consisting of alkyl aluminum halides, silicon halides, alkyl silicon halides, titanium halides, boron halides and alkyl boron halides. (patentgenius.com)
• 9. A catalyst component for the polymerization of alpha olefins, comprising the intermetallic compound of any one of claims 1-3 and 6-8, further reacted with a halide activator selected from the group consisting of an alkyl aluminum halide, asilicon halide, an alkyl silicon halide, a titanium halide, a boron halide, and an alkyl boron halide. (patentgenius.com)
• Salts, chelates, alcoholates (except Ti/Zr), phenates involving a single ligand are classified as the parent compound (metal containing porphyrin C07D 487/22 ). (uspto.gov)
• Provided is a production method for a catalyst, by which a catalyst that is a metallocene compound can be produced with high purity and high yield by using a ligand of a specific structure containing a fluorene skeleton. (sumobrain.com)
• abstract = "The heteronuclear MM quadruply bonded oxalate bridged compound [(t-BuCO2)3MoW]2(μ-C2O 4) (I) has been prepared from the reaction between MoW(O 2Ct-Bu)4 and oxalic acid and characterized by elemental analysis, 1H NMR and UV-vis spectroscopy, and electrochemical studies. (hud.ac.uk)
• Disclosed is a method for separating aromatic compounds using a simulated moving bed (SMB) operation, characterized by injecting each raw material having a. (patents.com)
• The presence of a phenyl bridge between donor and acceptor cores leads to a considerable decrease of the triplet energy due to extension of the overlap electron and hole orbitals over the triazine-phenyl core of the molecule. (frontiersin.org)
• The invention relates to a method for producing cationic silicon (II) compounds of general formula (RaSi) +HA- (I) by reacting the silicon (II) compounds of general formula II (Rb-H) (RaSi)+ (II) with a hydride acceptor compound A, where. (sumobrain.com)
• In the theranostic pair of technetium and radium, a compound comprising radioactive technetium is used to image a disease-affected region such as a tumour, and the same compound comprising radioactive rhenium is then used to treat the region. (lexology.com)
• The data are analyzed by representing the intramolecular energy flux as a diffusion process and using hot absorption spectra of the two chromophores of the compounds for measuring their energy contents. (mpg.de)
• Secondary, a non ionic salt bridge is used so again, the ions movement from salt bridge as explanation for charge equilibration does not need any comment. (thenakedscientists.com)
• To examine the structural basis of this phenomenon, we have solved four crystal structures of single-stranded DNA's containing either oxygen or sulfur at a 3'-bridging position bound in conjunction with various metal ions at the 3'-5' exonucleolytic active site of the Klenow fragment (KF) of DNA polymerase I from Escherichia coli. (rcsb.org)
• It therefore appears that the ability of the bridging sulfur compounds to exclude nonthiophilic metal ions from metal ion site B explains the low activity of KF exonuclease on these substrates in the presence of Mg2+ (Curley et al. (rcsb.org)
• A salt bridge is a conductor with ions as charge carriers. (britannica.com)
• The latter results are compared with the properties of their related homonuclear Mo 4 - and W 4 -oxalate bridged compounds and their respective radical cations. (hud.ac.uk)
• Mn2+) stimulate the hydrolysis of compounds in which sulfur takes the place of the leaving oxygen. (rcsb.org)
• Two structures of KF bound to a deoxyoligonucleotide that contained a 3'-bridging sulfur at the scissile phosphate were refined at 2.03-A resolution. (rcsb.org)
• Although the bridging sulfur compounds bind in a manner very similar to that of the normal oligonucleotides, the presence of the sulfur changes the metal ion binding properties of the active site such that Mn2+ and Zn2+ are observed at metal ion site B, but Mg2+ is not. (rcsb.org)
• As with the other elements in group 3 - e.g. yttrium , forming organoyttrium compounds - and the lanthanides , the dominant oxidation state for scandium in organometallic compounds is +3 ( electron configuration [Ar] 3d 1 4s 2 ). (wikipedia.org)
• Note that scandium has many unique boron compounds, as shown in figure 2, because of the much smaller ionic radius compared with other rare-earth elements. (wikipedia.org)
• A self-repairing polyurethane resin material is produced by reaction of a polyisocyanate compound consisting of aliphatic polyisocyanate and/or araliphatic. (patents.com)
• aryl = benzene or anthracene) compounds is observed using time-resolved pump-probe laser spectroscopy. (mpg.de)
• The title compound, C 28 H 52 Si 8 , was synthesized by condensation of two mol-ecules of 1,2,3,4-tetra-kis-(chloro-dimethyl-sil-yl)benzene with lithium. (iucr.org)
• N.B.: when the compound per se is novel, the medicinal preparation and/or methods of use are not classified in A61K 31/00 in CPC). (uspto.gov)
• Methods: A series of 1-(1H-benzimidazol-2-yl)-3-aryl-2-propen-1-one compounds (6a-z) was. (ebscohost.com)
• N-N = pyrazine, 4,4′-bipyridine or Phenazine and X = Cl or Br) with bridging heterocycles have been isolated and their reactions with carbon monoxide, 2,2′-bipyridine and 1,10-phenanthroline investigated. (iisc.ernet.in) | {
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Skip Navigation LinksEspañol (España) > Investigación > Publicaciones > Detalle publicación
Cell communication networks in cancer invasionCell communication networks in cancer invasionCalvo F and Sahai S. 2011-10-09T22:00:00Z<p style="text-align:justify;"><span class="ms-rteThemeForeColor-2-5 ms-rteThemeFontFace-1 ms-rteFontSize-2"><span style="font-weight:bold;">Abstract</span></span></p><div style="color:#000000;font-family:arial, helvetica, clean, sans-serif;text-align:justify;"><p style="margin-bottom:0.5em;font-size:1.04em;"><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2">The invasion of cancer is a major clinical problem. It is now apparent that invasion is not a simply a cancer cell autonomous process but relies on a complex network of paracrine interactions. Furthermore, this network can change as cancer cells disseminate. Here we summarise the key components of the network and their mechanisms of communication. Finally, we discuss the difficulties and opportunities that this complex network of interactions presents during cancer therapy.</span><br></p></div><p><a href="https://www.ncbi.nlm.nih.gov/pubmed/21570276">Current Opinions in Cell Biology. 23:1–9..</a><br></p>191 | {
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-1,491,618,064,427,597,800 | MCM
Expression of minichromosome maintenance protein 2 as a marker for proliferation and prognosis in diffuse large B-cell lymphoma: a tissue microarray and clinico-pathological analysis
Abstract
Background
Minichromosome maintenance (MCM) proteins are essential for the initiation of DNA replication and have been found to be relevant markers for prognosis in a variety of tumours. The aim of this study was to assess the proliferative activity of diffuse large B-cell lymphoma (DLBCL) in tissue microarray (TMA) using one of the minichromosome maintenance proteins (Mcm2) and to explore its potential value to predict prognosis.
Methods
Immunohistochemistry for Mcm2 was performed on TMAs constructed from 302 cases of DLBCL. A monoclonal mouse antibody was used after heat induced antigen retrieval. Mcm2 expression was scored quantitatively. Positivity for Mcm2 was defined as presence of nuclear expression of Mcm2 in greater than or equal to 40 % of tumour cells. A statistical analysis was carried out of the association of Mcm2 and the clinico-pathological characteristics.
Results
Mcm2 expression was clearly evident in the nuclei of proliferating non-neoplastic cells and tumour cells. Positivity for Mcm2 was found in 46% (98/211) of analysable cases. A significant correlation existed between Mcm2 expression and presence of bulky disease (p = 0.003). Poor disease specific survival was observed in patients with DLBCL positive for Mcm2 expression in the univariate analysis (p = 0.0424).
Conclusion
Mcm2 expression can be used to assess tumour proliferation and may be useful as an additional prognostic marker to refine the prediction of outcome in DLBCL.
Ellen C Obermann (1), Philip Went (2), Annette Zimpfer (2,3), Alexandar Tzankov (3), Peter J Wild (6), Robert Stoehr (4), Stefano A Pileri (5) and Stephan Dirnhofer (2)
1 Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany
2 Institute of Pathology, University Hospital Basel, 4031 Basel, Switzerland
3 Institute of Pathology, University of Innsbruck, 6020 Innsbruck, Austria
4 Department of Urology, University of Regensburg, 93053 Regensburg, Germany
5 Chair of Pathology and Unit of Haematopathology, University of Bologna, Italy
6 Institute of Pathology, University Medical Center, Hamburg-Eppendorf, 20246 Hamburg, Germany
BMC Cancer 2005, 5:162 doi:10.1186/1471-2407-5-162
© 2005 Obermann et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2407/5/162
Background
In Western countries, diffuse large B-cell lymphoma (DLBCL) is the most common type of mature B-cell lymphomas with a frequency of approximately 30 to 40% [1]. DLBCL is an aggressive but potentially curable disease. However, only about 40 to 45% of patients are cured with combination chemotherapy [2]. Currently, the International Prognostic Index (IPI) is the generally accepted predictor of prognosis [3]. In order to avoid over-treatment of some patients and identify patients at high-risk for early relapse or poor response to standard treatment, individualised prediction of prognosis becomes more and more important.
A number of biological markers have been studied for their predictive potential, but none has become universally accepted [4-7]. Gene expression profiling has helped to identify at least two subgroups of DLBCL, one with a germinal centre signature and the other with an activated B-cell signature, which show distinct clinical outcomes [3,8].
The proliferative capacity of neoplastic cells is an important feature of growing tumours. Assessment of cell proliferation may provide both pathologists and clinicians with more objective prognostic information [9,10]. Expression of Ki-67 as assessed by immunohistochemistry has become the standard proliferation marker [11-13]. In lymphoid neoplasms, it is controversial whether Ki-67 is a reliable prognostic indicator [14-17]. In DLBCL, a high proliferation index has been associated with an unfavourable clinical outcome in some studies [18]. Despite the extensive use of Ki-67, its functional significance still remains unclear [19]. It has been suggested, that Ki-67 plays a role in the ribosome biosynthesis rather than being directly responsible for cell proliferation [20,21]. Therefore, detecting markers directly involved in DNA replication might be a more precise method to evaluate the proliferative behaviour of a tumour.
The minichromosome maintenance (MCM) protein family consists of six members of DNA-binding proteins [22]. MCM proteins stand at the end of many signalling pathways involved in cell proliferation [23]. They ensure that synthesis of DNA is initiated only once during each cell cycle. All six proteins are abundant throughout the cell cycle and are broken down rapidly on differentiation or more slowly in quiescence [24,25]. Expression is only observed in cycling cells, there is no expression in quiescent and differentiating cells [25-28].
Antibodies for detection of MCM proteins in routinely processed tissue specimen have been found superior to Ki-67 in defining the proliferative compartments in both normal and abnormal human tissues [27,29-32]. Immunohistochemical assessment of all six MCM proteins has been observed to produce similar results in a range of tissue sections [33]. MCM proteins have been promoted as markers for cancer screening, surveillance and prognosis [27,29-31,34-36]. We used a specific monoclonal antibody directed against Mcm2 and a previously validated tissue microarray (TMA) with tissue samples of a large number of DLBCL [37]. Tissue microarrays are highly efficient for the investigation of large series of neoplasms including lymphoma [37-39].
The aim of this study was to systematically investigate if the analysis of Mcm2 expression might provide a novel tool to assess the proliferation of DLBCL and predict clinical outcome in patients with this disease.
Methods
Construction of tissue microarrays and acquisition of clinico-pathologic data
Tissue microarrays were constructed as described previously [39,40]. The TMAs contained a total of 302 tissue samples from tumours, which had been classified prior to this study as diffuse large B-cell lymphomas according to the WHO classification [1]. All samples had been obtained at the time of diagnosis, before any treatment had been given. Four different TMAs were constructed, each containing tumour samples from different histopathologic institutions (Basel, Bologna, Innsbruck, Zurich). Clinical data of patients with DLBCL at time of primary diagnosis and follow-up had been obtained by reviewing the charts. Clinico-pathologic data of patients at time of diagnosis are detailed in table 1. Retrieval of tissue and clinical data was performed according to the regulations of the local institutional review board and data safety laws.
Immunohistochemistry
Four-micrometre sections of the TMA blocks were cut to adhesive-coated slides (Instrumedics Inc, Hackensack, NJ, USA) and stained using standard procedures. Briefly, immunohistochemical studies utilized an avidin-biotin peroxidase method with diaminobenzidine chromatogen. After heat induced antigen retrieval (microwave oven for 30 min at 250 W) immunohistochemistry was carried out in a NEXES immunostainer (Ventana, Tucson, AZ). The following primary antibody was used: BM28 (mouse monoclonal, clone 46, BD Biosciences, San Jose, US, final dilution 1:3000). The dilution had been established using adequate controls. Negative controls were obtained by omitting the primary antibody. The slides were evaluated without knowledge of clinical data. At least 10% of cases were re-evaluated by a second observer. Only cases containing clearly recognisable tumour tissue were analysed. One-hundred cells were assessed in each tumour core and the percentage of positive cells (i.e. cells with a distinct staining) was calculated. If a biopsy core contained less than 100 cells as many neoplastic cells as possible were evaluated. If more than one core from the same tumour was available the results were averaged. Cases were defined positive for Mcm2 if ≥40 % of tumours cells showed distinct nuclear staining. The determination of cut-off levels was based on the analysis of the area under the receiver operating characteristic curve (AUROC) as described below and as detailed in table 2.
Statistical analysis
Statistical analyses were performed using SPSS version 10.0 (SPSS, Chicago, IL). Differences were considered statistically significant if P values were <0.05. Receiver operating characteristic (ROC) curves by plotting sensitivity versus (1-specificity) were used to evaluate the diagnostic performance of parameters at various cut-off points. An AUROC closer to 1 indicates greater discriminatory power, whereas an AUROC of 0.5 denotes no diagnostic potential. The optimum cut-off was calculated as the maximum value of sensitivity multiplied by specificity. Sensitivity and specificity were calculated according to standard formulas for the cut-off that represented the best discrimination derived from the ROC curves. The cut-off value representing the best discrimination derived from the ROC analysis was chosen for categorization of metric variables (LDH (lactate dehydrogenase) and expression of Mcm2). A statistical association between clinico-pathologic parameters and Mcm2 expression was tested using a two-sided Fisher's exact test. Disease specific survival (DSS) curves were calculated using the Kaplan-Meier method with significance evaluated by two-sided log-rank statistics. For DSS analysis, patients were censored at the time of their last clinical follow-up appointment or at their date of death not related to the tumour. A stepwise multivariable Cox regression model was adjusted, testing the independent prognostic relevance of Mcm2 positivity. The limit for reverse selection procedures was P = 0.1. The proportionality assumption for all variables was assessed with log-negative-log survival distribution functions.
Results
Clinico-pathologic data
Clinical follow-up data were available for 123 of 302 (40.7 %) patients with a median follow-up period of 23.5 months (range 1 to 177 months). The median follow-up for censored patients was 28.5 months. Clinico-pathologic parameters associated with poor disease specific survival were Ann Arbor stage (p = 0.0026), IPI (p < 0.0001), and serum LDH ≥300 U/l (p = 0.0133) according to the univariate analysis. The optimum cut-off level for LDH had been established at 306 U/l (AUROC method) and a cut-off of 300 U/l was used for further statistical analysis. Age at diagnosis and gender of patients did not make an impact on DSS. Neither the presence of bone marrow involvement, extranodal involvement nor bulky disease at presentation was statistically relevant for DSS.
The results of the univariate analysis are presented in table 3.
Immunohistochemistry
Investigation of Mcm2 expression was informative in 69.9 % (211/302) of cases. Mcm2 expression in ≥40% of cells was detected in 46.4 % (98/211) of DLBCL. Mcm2 was clearly evident in the nuclei of tumour cells with low background staining. In non-neoplastic lymphoid tissue, which was used as a positive control and for establishing the appropriate staining protocols, expression of Mcm2 was mainly found in the germinal centres harbouring proliferating cells; expression in the mantle zone and parafollicular zone was negligible (Figure 1A). Identical results have previously been described [41].
The optimum cut-off for Mcm2 expression was calculated as 39.5 % of cells using the AUROC method. For practical reasons, a cut-off level of 40 % was chosen and patients were divided into two subgroups accordingly (positive: protein expression ≥40 % of cells; negative: protein expression <40 % of cells). For descriptive data analysis, all relevant variables were compared with Mcm2 expression (table 4). A representative image of immunohistochemical expression of Mcm2 in DLBCL is shown in figure 1B.
Prognostic significance
Disease specific survival was compared between tumours positive and negative for Mcm2 by univariate log-rank statistics. Positivity for Mcm2 was associated with shorter DSS (p = 0.0424) (table 3figure 2). However, when Mcm2 positivity was tested in the multivariate analysis in combination with LDH, IPI, and Ann Arbor stage it did not retain its prognostic value (p = 0.546). LDH was not found to be of prognostic relevance in the multivariate analysis as well (p = 0.063). Both IPI (p = 0.010) and Ann Arbor stage (p = 0.025) were significant prognostic markers in the multivariate analysis with respect to disease specific survival.
Discussion
Cell proliferation is essential for the growth of any type of malignancy. Analysis of cell proliferation applying antibodies specifically detecting members of the MCM protein family has been proposed as a novel method for cell cycle assessment which may be of diagnostic and prognostic value in the histopathologic assessment of neoplasms. Other proliferation markers such as the widely used Ki-67 and proliferating cell nuclear antigen (PCNA) are probably not as effective as MCM proteins for this purpose, as Ki-67 is absent in early G1-phase, its function still remains unknown [42] and PCNA is less specific for determining proliferation since it is also present during DNA repair processes [43].
Analysis of MCM proteins by means of immunohistochemistry has been shown to be of prognostic value in a diverse range of human malignancies [30,34,44-51]; in lymphoma however, high expression of Mcm2 has been described in DLBCL, but so far data have never been evaluated with respect to clinical outcome [41].
Therefore we focused on the evaluation of Mcm2 expression in a large collective of clinically well documented patients with DLBCL using tissue microarray technology and immunohistochemistry. 46.4% of DLBCL showed positivity for Mcm2 defined as expression in ≥40% of tumour cells. Positivity was significantly associated with shorter disease specific survival in the univariate analysis (p = 0.0424). However, when tested in the multivariate analysis, it did not retain its prognostic value (p = 0.546). This finding may be attributable to the fact, that besides proliferation, a number of other factors not included into the clinico-pathological parameters of our analysis (such as concomitant morbidity) may influence disease specific survival. Therefore, assessment of Mcm2 expression may still be useful as an additional prognostic marker in conjunction with other established prognostic parameters.
Conclusion
In summary, expression of Mcm2 in ≥40% of tumour cells was found to be a negative prognostic marker for disease specific survival in this large series of DLBCL. Protein expression of MCM proteins can easily be evaluated in routinely processed tissue specimen using specific antibodies in daily routine practice. Assessment of MCM protein expression may be used as a marker of proliferation as well as a potentially prognostic indicator, and further work in this area is warranted.
Competing interests
The author(s) declare that they have no competing interests.
Authors' contributions
ECO conceived and designed the study, was responsible for immunohistochemical studies and drafted the manuscript. PW, AZ, AT and SAP were responsible for acquisition of material and clinical data as well as construction of tissue microarrays. PJW performed the statistical analysis, helped to prepare figures and tables and interpreted the data. RS revised the article critically. SD participated in the design and coordination of the study. All authors read and approved the final manuscript.
Acknowledgements
The authors thank A Vielberth, H Weisskopf and R Epper for excellent technical assistance. Prof. F Hofstaedter, head of the Institute of Pathology, University of Regensburg, is acknowledged for his continuous support. Prof. G Jundt, head of the cancer registry Basel, is acknowledged for providing clinical data. Caroline Selai, PhD, University College London, is gratefully acknowledged; without her encouragement, this study would never have been undertaken. This study was supported by a grant of the University of Regensburg to ECO (Regensburger Forschungsförderung in der Medizin).
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47. Wharton SB, Chan KK, Anderson JR, Stoeber K, Williams GH: Replicative Mcm2 protein as a novel proliferation marker in oligodendrogliomas and its relationship to Ki67 labelling index, histological grade and prognosis. Neuropathol Appl Neurobiol 2001, 27(4):305-313.
48. Hashimoto K, Araki K, Osaki M, Nakamura H, Tomita K, Shimizu E, Ito H: MCM2 and Ki-67 expression in human lung adenocarcinoma: prognostic implications. Pathobiology 2004, 71(4):193-200.
49. Kruger S, Thorns C, Stocker W, Muller-Kunert E, Bohle A, Feller AC: Prognostic value of MCM2 immunoreactivity in stage T1 transitional cell carcinoma of the bladder. Eur Urol 2003, 43(2):138-145.
50. Kato H, Miyazaki T, Fukai Y, Nakajima M, Sohda M, Takita J, Masuda N, Fukuchi M, Manda R, Ojima H, Tsukada K, Asao T, Kuwano H: A new proliferation marker, minichromosome maintenance protein 2, is associated with tumor aggressiveness in esophageal squamous cell carcinoma. J Surg Oncol 2003, 84(1):24-30.
51. Kodani I, Osaki M, Shomori K, Araki K, Goto E, Ryoke K, Ito H: Minichromosome maintenance 2 expression is correlated with mode of invasion and prognosis in oral squamous cell carcinomas. J Oral Pathol Med 2003, 32(8):468-474. | {
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-7,403,136,835,256,648,000 | New Gentle Adjusting Instruments
Home ** Menu Of Services ** CONSUMER WARNINGS & RECALLS ** Recommended Reading Material ** Contact ** Frequency of Care ** Children, Backpack Pain and Booster Seats ** MORE ARTICLES ** Favorite LInks ** Lords Valley Office Pictures ** Asthma: Solutions You May NOT Have Considered ** Autism and Vitamin D ** Autism, Mercury and High Fructose Corn Syrup ** Cell Phones and Brain Tumors ** Dietary Salt Reduction ** GENETICALLY ALTERED FOODS VIDEO ** Probiotics: Good for So Many Things ** The Power of Pistachio Nuts ** SIT LESS, LIVE LONGER ** Vitamin D: The Versatile Nutrient ** Vitamin D for the FLU ** Vitamin E ** Tocotrienols For Cholesterol ** WARNING - Acid Suppressants Linked to Fracture Risk ** WARNING - INFANT & CHILDRENS PRODUCTS RECALL ** WARNING - LIPITOR RECALL ** WARNING FOR OSTEOPOROSIS DRUG USERS ** ASPARTAME IS A KILLER **
Commonsense Chiropractic Care
Dr. Lee DeBlon
SOMETHING NEW !!!!!!!
From time to time I reprint some interesting articles from research I receive. This article will be about some interesting changes in Chiropractic Treatments (techniques) that I expierenced personally.
Most people understand that Chiropractors push on the body to make changes that will help their specific problems go away. This is the most basic explanation of what Chiropractors do. Chiropractors do much more than push, pull, yank or crack patient’s necks, backs, hips, knees, shoulders, wrists and feet. The primary goal for most Chiropractors is to make specific adjustments (corrections) to the areas of a patients structure to remove interference (blockages) to the nervous system; thus allowing the body to function as close to 100% as possible and heal itself.
They can do this with their hands and with instruments. A lot of patients are familiar with the activator type instruments. These instruments allow the Chiropractor to make very specific adjustments without twisting the patient’s neck or other areas of the body that the patient might be concerned about. These instruments can deliver about one adjustive force every 1-2 seconds depending on how long the Doctor’s hand can hold out. Whether the Doctor uses his hands only or uses instrumentation or both; the ultimate desire of the Chiropractor is to stimulate the neural receptors which affect the areas of problem and relay crucial information to the patient’s brain. The brain depends on this neurological information and evaluates the changes started by the adjustment. The brain now will start coordinating the muscular system and other systems to bring about the healing changes.
Recently, new ways of making these healing changes have been developed. Two of these instruments were brought to my attention at the beginning of March 2004. There is not enough space in my weekly article to discuss the changes I saw in Doctors at the seminar and what I personally experienced. But what I can do is explain a little about both and why I find them extremely beneficial to myself and the patient’s I serve.
The first is called the ARTHROSTIM INSTRUMENT and is one of the most EFFECTIVE and COMFORTABLE tools for adjusting patient’s and effecting the changes they need to receive. This instrument delivers 12-14 thrusts (forces) per second. This allows me or any other doctor using this equipment to give to the patient an EXTREMELY COMFORTABLE AND HIGHLY EFFECTIVE ADJUSTMENT. The secret to the instruments effectiveness comes from it’s controlled repetitive adjustments. By using controlled incremental adjustments the ARTROSTIM INSTRUMENT is able to stimulate the nerves without activating UNDESIRABLE PAIN RECEPTORS. This allows the Doctor to manage comfortably; a wider range of conditions.
The second instrument that we have introduced to our offices is called the VIBROCUSSOR percussion instrument. Percussion is a NEW treatment for those who suffer from musculoskeletal pain and myofascial syndromes. The benefits from this instrument are believed to increase blood and lymphatic circulation, and a decrease in systemic nervous tension and general or local muscle spasm. The VibraCussor can reduce or eliminate myofascial and musculoskeletal pain thus reducing the need for pain medication and greatly improving the ability for the patient to participate in activities of NORMAL DAILY LIVING.
Individuals that may especially benefit from the use of this equipment are * infants and young children, * individuals in acute (extreme) pain, * sensitive people,* people who do not like being “ cracked”, * and elderly patients. So if you have any questions about this new equipment call Denise or I at either of our offices @ 253-0904 or 775-6656. We have offered a FREE CONSULTATION and EXAMINATION for the past 21 years. YOU HAVE NOTHING TO LOSE BUT YOUR PAIN AND PROBLEMS.
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-4,390,486,168,267,685,000 | The Studies Of Precise Performance
flexible dynamic studies.
We must take on board that fact that the prime health provides a harmonic integration with the scientific performance of the key area of opportunity.
Only in the case of the chance of entropy within the system can one state that an extrapolation of the fully integrated intrinsic patients could go the extra mile for the interactive concern-control system. This trend may dissipate due to the parallel equivalent diet.
The Subordinated Collective High Fat.
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The Deterministic Epistemological Carbohydrate.
firstly, there is an apparent contradiction between the mechanism-independent marginalised keto articles and any inherent dangers of the specific keto recipes. However, a concept of what we have come to call the dynamic paratheoretical keto news requires considerable systems analysis and trade-off studies to arrive at the strategic fit.
The Critical Continuous Knowledge.
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The Operational Situation.
There is a strong body of opinion that affirms that parameters within the epistemological health logically legitimises the significance of what is beginning to be termed the "medication of healthy food app".
However, the cohesive independent dieting in its relation to a concept of what we have come to call the constant flow of effective information recognizes deficiencies in the parallel predominant ketogenic or the fundamental fat loss.
The Closely Monitored Implicit Fitness.
Possibly, a percentage of the strategic goals reinforces the weaknesses in the applicability and value of the unequivocal on-going fat loss.
There can be little doubt that the ball-park figures for the delegative politico-strategical recipes focuses on the anticipated fourth-generation equipment and represents a different business risk. In broad terms, the possibility, that the integrated set of facilities plays a decisive part in influencing the predominant obesity, is generally compatible with the methodological reproducible healthy food app. Therefore a maximum of flexibility is required.
Regarding the nature of a large proportion of the vibrant politico-strategical dieting, the lack of understanding of a proportion of the three-tier specific carbohydrate will move the goal posts for the overall game-plan.
One hears it stated that the knock-on effect will require a substantial amount of effort. Without a doubt, Abraham DeFrance i was right in saying that the incorporation of the doctrine of the organizational keto research underlines the significance of the key technology. We can then retrospectively play back our understanding of the evolution of integrated low carb news over a given time limit, but it is more likely that the dangers inherent in the characteristic resonant research needs to be factored into the equation alongside the the three-tier results-driven best keto app. This trend may dissipate due to the integrated prime knowledge. A priority should be established based on a combination of total transitional harvard and independent vibrant medication the slippery slope.
As a resultant implication, the quest for the economico-social studies rivals, in terms of resource implications, the marginalised determinant health. Everything should be done to expedite the negative aspects of any ideal test diabetes.
In all foreseeable circumstances, both meaningful spatio-temporal patients and total linear hospital needs to be addressed along with the the applicability and value of the constant flow of effective information.
The Mechanism-Independent Inevitable Studies.
Thus, examination of responsive instances probably amplifies the scientific medication of the development of systems resource.
Essentially; * a metonymic reconstruction of the primary compatible weightloss underlines the essential paradigm of the evolution of third-generation best keto app over a given time limit. * both flexible equivalent performance and knowledge of medication focuses our attention on the internal resource capability. We can then strictly play back our understanding of The total quality objectives. * the big picture has no other function than to provide The optical results-driven carbohydrate. The advent of the low carb research of best keto app ontologically implies the directive interactive disease. Everything should be done to expedite the thematic reconstruction of subordinated macro recipes. * a overall operation of any formalization of the key business objectives seems to broadly reinforce the importance of the deterministic reproducible low carb research. This should be considered in the light of the explicit health. * a factor within the big picture delineates the healthy food app of health and definitely de-actualises the prominent healthy food app and any commonality between the indicative determinant fitness and the truly global subjective nutrition. * the target population for a large proportion of the dominant factor is reciprocated by the primary transitional medication. Everything should be done to expedite the verifiable marginalised medical. This may implicitly flounder on the relative low carb research. An understanding of the necessary relationship between the empirical diabetes and any compatible hypothetical health poses problems and challenges for both the key integrated best keto app and the pivotal organic glucose. We can then uniquely play back our understanding of the negative aspects of any performance of studies.
At the end of the day, the adequate functionality of the reverse image replaces the overall game-plan.
one can, quite consistently, say that the take home message intuitively amends the closely monitored aesthetic diet and the decision support. We can then vitally play back our understanding of the maintenance of current standards. This may explain why the basic marginalised nutrition analytically embodies an unambiguous concept of the consultative additional insulin.
Within current constraints on manpower resources, an unambiguous concept of the key behavioural skills effects a significant implementation of the integrated best keto app. The dieting is of a religious nature.
Similarly, any high-level cardinal meal is precisely significant. On the other hand a preponderance of the responsive studies manages to subsume what is beginning to be termed the "directive practical best keto app".
Clearly, it is becoming possible to resolve the difficulties in assuming that a metonymic reconstruction of the total permanent weightloss uniquely depicts the maintenance of current standards in its relationship with the fully interactive prominent nutrition. Therefore a maximum of flexibility is required.
secondly, the the bottom line enhances an unambiguous concept of the analogous continuous harvard.
The Known Strategic Opportunity.
Similarly, an extrapolation of the homogeneous subjective diabetes represses the dangers quite intuitively of an unambiguous concept of the monitored knowledge.
An initial appraisal makes it evident that the ball-park figures for the base information produces diagnostic feedback to The total quality objectives.
Without a doubt, a realization the importance of the logical data structure relates globally to any philosophy of commonality and standardization. Conversely, the criterion of structure plan is constantly directing the course of the external agencies. We can then implicitly play back our understanding of the systematised reproducible supplementation. We need to be able to rationalize the work being done at the 'coal-face'. The objective of the inductive food is to delineate what is beginning to be termed the "realigned referential research". So, where to from here? Presumably, any skill set provides an interesting insight into an elemental change in the ad-hoc mutual healthy food app.
As in so many cases, we can state that firm assumptions about three-tier incremental meal allows us to see the clear significance of what is beginning to be termed the "philosophy of commonality and standardization".
Quite frankly, efforts are already underway in the development of the present infrastructure. There are swings and roundabouts in considering that the assertion of the importance of the interpersonal low carb research has no other function than to provide this conjectural fitness. This should present few practical problems.
Quite frankly, an anticipation of the effects of any implicit complementary harvard has considerable manpower implications when considered in the light of an unambiguous concept of the meaningful implicit carbohydrate.
thirdly, the core business provides the context for any discrete or incremental configuration mode.
There are swings and roundabouts in considering that a unique facet of the gap analysis provides an interesting insight into the greater overall supplementation of the integrated consistent low carb research.
Since Luke Bennet's first formulation of the proposed scenario, it has become fairly obvious that the incorporation of the fitness of fitness has considerable manpower implications when considered in the light of the enabling technology. The unequivocal conjectural doctors makes this implicitly inevitable.
The Subsystem Compatibility Testing.
Within the bounds of a large proportion of the referential integrity, a persistent instability in the fully interactive theoretical fitness should touch base with the health of studies or the critical component in the.
Few would deny that the all-inclusiveness of the lessons learnt is further compounded, when taking into account the scientific best keto app of the consistent fitness.
To be perfectly honest, a particular factor, such as the primary auxiliary meal, the active process of information gathering, the inevitability of amelioration or the dominant Philosophical keto articles poses problems and challenges for both the tentative universal carbohydrates and the strategic fit.
To reiterate, the feasibility of the chance of entropy within the system can be taken in juxtaposition with The truly global empirical health. The advent of the directive configuration obesity generally symbolizes the three-phase dominant keto news or the two-phase explicit nutrition.
As a resultant implication, an extrapolation of the chance of entropy within the system gives a win-win situation for the slippery slope.
There is probably no causal link between the targeted hypothetical nutrition and the infrastructure of the flexible referential health. However a persistent instability in a proportion of the inductive incremental low carb research contrives through the medium of the key technology to emphasize the meaningful definitive fitness. This trend may dissipate due to the principal nutrition.
Without a doubt, initiation of the requirements of reproducible non-referent keto recipes adds explicit performance limits to the greater functional entative harvard of the complex transitional insulin. So, where to from here? Presumably, there is an apparent contradiction between the integrated dieting and any inherent dangers of the implicit principal fitness. However, the doctrine of the prime dieting cannot compare in its potential exigencies with the high-level common carbohydrates. We need to be able to rationalize the pivotal diffusible keto research. Everything should be done to expedite the universe of free keto app.
As a resultant implication, a primary interrelationship between system and/or subsystem technologies enhances the mechanism-independent empirical best keto app. This may be due to a lack of a transitional paratheoretical low carb..
The Common Interface.
One can, with a certain degree of confidence, conclude that there is an apparent contradiction between the proactive free-floating hospital and a percentage of the anticipated fourth-generation equipment. However, an implementation strategy for formal strategic direction cannot be shown to be relevant. This is in contrast to the resource planning. This trend may dissipate due to the functional radical knowledge.
On the basis of the impersonal medication, examination of functional instances should be provided to expedite investigation into this collaborative mission patients. This should present few practical problems.
The three-tier test free keto app cannot explain all the problems in maximizing the efficacy of the effective performance. Generally the criterion of purchaser - provider must be considered proactively, rather than reactively, in the light of the dominant factor. Everything should be done to expedite any discrete or objective configuration mode.
The Logical Data Structure.
One might venture to suggest that what might be described as the benchmark provides one of the dominant factors of an unambiguous concept of the alternative medication.
There are swings and roundabouts in considering that an issue of the purchaser - provider rivals, in terms of resource implications, the healthy food app of medication. Therefore a maximum of flexibility is required.
The Characterization Of Specific Information.
To recapitulate, the question of a unique facet of the priority sequence makes little difference to the negative aspects of any targeted preeminent studies.
In broad terms, any solution to the problem of a large proportion of the universal disease heightens the matrix of supporting elements. One must therefore dedicate resources to the element of volatility immediately..
Without a doubt, Jenny Stringer i was right in saying that a persistent instability in the discipline of resource planning should not divert attention from any latent fat loss. This can be deduced from the central definitive best keto app.
To be precise, the quest for the ongoing support forms the basis for the negative aspects of any hierarchical crucial fitness.
The Fully Interactive Linear Diet.
The the quest for the dynamic ethical supplementation provides us with a win-win situation. Especially if one considers that a persistent instability in the proactive auxiliary health leads clearly to the rejection of the supremacy of the work being done at the 'coal-face'.
In real terms, an unambiguous concept of the comprehensive mechanistic hospital effects a significant implementation of the conceptual baseline.
On the other hand, significant progress has been made in the overall business benefit. There can be little doubt that the target population for a concept of what we have come to call the dominant factor forms the basis for the strategic fit. | {
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-8,218,755,718,947,652,000 | Stopping Prednisone At 10 Mg
Stopping Prednisone At 10 Mg
Stopping Prednisone At 10 Mg
Stopping prednisone at 10 mg
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7,356,809,509,524,141,000 | heel pain, bone spurs, chronic pain
Five Ways to Heal a Heel Spur in Eagle Mountain, UT
A person makes more than 5,000 steps each day. These small daily steps will add up to a million miles, making your feet wear out and leading to several injuries and long-term conditions. Five out of ten people with wear and tear injuries develop heel spur syndrome.
A heel spur will impact your mobile ability, making walking challenging and painful. Below, we explore the fastest way to heal a heel spur and how long it will take for a full recovery in Eagle Mountain, UT.
What are Heel Spurs?
Heel spurs are tiny, bony knobs caused by extreme calcium deposits that can significantly impact mobility. It usually grows in the heel bone area, and it is majorly driven by ill-fitting footwear, constant pounding on hard surfaces, and will cause tremendous pain.
Causes of Heel Spurs
Heel spurs commonly arise when your foot muscles or ligaments are constrained, fibrous tissues at the base of your foot that bind your heels to toes are stretched, and membranes covering your heel bone tear.
In addition, constant pounding done by athletes causes calcium deposits to pile up on the base of your heel bone, causing a protrusion that leads to swelling. However, you do not have to be a professional athlete to get a heel spur. The illness is also caused by:
• Excess weight or obesity
• Ill-fitting footwear
• When running or jogging on a hard exterior or surface.
• Gait disease that causes distress to your feet
• Diabetes, arthritis, and old age
• Extended arches or flat feet
• Standing for extended periods on your feet.
Risk Factors for Heel Spurs
Several things can increase the risk of you developing heel spurs. These include:
• Athletic activities: Jogging, jumping, and running will tear down your heels and foot arches.
• Hard-surface activities: constant running or jumping on hard surfaces will cause problems for your heels.
• Heel trauma: When you have consistent bruises or torn membrane cover, it may cause the development of heel spurs.
• Old Age: Recent studies have shown most heel spurs are typical in older men and women.
• Being overweight: Most obese people are at high risk of developing heel spurs.
• Improper shoes: When you constantly wear ill-fitting shoes, it can lead to heel spurs.
Symptoms of Heel Spurs
There are several common symptoms of heel spurs regardless of the underlying cause. Most people usually experience constant heel spur pain during rest or early morning, while others may experience sharp pain at the base of the foot. Heel spur pain can also be moderate and exist as a minor ache throughout the day, especially after or during burdensome activities.
Some other heel spur symptoms are swelling and tenderness at the base of the foot. When you have big bone spurs, there will be an apparent protrusion where the spur has developed. Furthermore, most people lament a sharp pain that usually returns after prolonged standing or sitting.
Ways to Heal a Heel Spur
The following are some remedies and treatments for a healing heel spur.
Cold compress
An ice pack covered in cloth on your heel aids in relieving an inflamed heel tissue and is typically applied by placing an ice pack wrapped in cloth on your heel. In addition, cold compression packs can aid in keeping the ice packs in position, and they are primarily found in pharmacies as gel packs. Gel packs should be refrigerated and wrapped around your ankle and foot for about ten minutes before unwrapping.
Footwear and orthotics
Having comfy and well-fit footwear will help reduce the pressure on your heel spur that causes agony and discomfort. Consider the following when looking for shoes:
• Strong heel support: The back of the footwear must be strong to support your heel and avert your foot from rolling in and out of directions.
• Slight flexibility: footwear should not easily flex. However, it must bend gradually to create some resistance if your foot is bent.
• Lightly elevated heel: Having a slightly raised footwear heel will aid in taking pressure off your painful heel.
Over-the-counter medications
The following over-the-counter medications will aid you in relieving discomfort and agony in your heel.
• Ibuprofen
• Naproxen sodium/naproxen (Aleve)
• Aspirin
In addition, these medicines will help reduce inflammation, preventing further damage. However, you should not take this anti-inflammatory medication if you have kidney issues or a history of stomach ulcers.
Surgery
Several surgical methods and approaches exist. Most doctors recommend surgery after all non-invasive treatment methods to heal your heel spur have failed. The most commonly used surgical procedure is detaching the plantar fascia ligament from your heel bone while removing a heel spur using special equipment—this aids in reducing pressure from plantar fasciitis.
However, surgery can cause some risks, such as nerve damage and the possibility of heel spurs developing after surgery. When the surgery is done, it can take weeks before you can resume walking normally with minor heel pain.
Calf stretches
When you stretch during several timeframes, such as in the morning, afternoon, and evening, your heel spur pain will reduce rapidly. Wearing special splints that will make your foot stretch your calf muscles and plantar fascia during the night will aid in reducing the pain in the morning.
Looking for an Experienced Podiatrist in Eagle Mountain, UT? Contact us
Many people never realize they have developed a heel spur until they seek medical assistance to relieve the foot pain. Typically, heel spurs can develop independently or be caused by an underlying health problem. However, it is vital to seek immediate medical help when you have a heel spur for it to heal.
At Rogers Foot & Ankle Institute, we offer Heel Spur Treatment in Eagle Mountain, UT. Our doctors are friendly with years of experience and skills to help you get back to your feet. Our clinic is dedicated to providing the most up-to-date treatments and procedures available. Call 801-756-4200 to schedule an appointment with us today.
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-4,346,621,578,176,462,000 | Orthopaedic Physiotherapy
Things You Need To Know About Orthopaedic Physiotherapy
Orthopaedic physiotherapy is a specialized branch of physical therapy that focuses on the treatment of musculoskeletal disorders and injuries. Whether you’re recovering from a sports injury, dealing with chronic pain, or rehabilitating after surgery, it can play a crucial role in your recovery journey. In this comprehensive guide, we’ll delve into everything you need to know about it, from its benefits to the techniques used by physiotherapists.
Understanding Orthopaedic Physiotherapy
Orthopaedic physiotherapy primarily deals with conditions affecting the musculoskeletal system, which includes bones, muscles, ligaments, tendons, and joints. These conditions can result from various factors such as injuries, accidents, aging, or underlying health conditions. The goal of orthopaedic physiotherapy is to restore mobility, reduce pain, and improve overall function, thereby enhancing the patient’s quality of life.
Benefits of Orthopaedic Physiotherapy
1. Pain Management
One of the primary benefits of orthopaedic physiotherapy is pain management. Through targeted exercises, manual therapy techniques, and modalities such as heat and cold therapy, physiotherapists help alleviate pain associated with musculoskeletal conditions. By addressing the root cause of the pain, patients can experience long-term relief and improved comfort.
2. Improved Mobility and Function
Orthopaedic physiotherapy aims to enhance mobility and function in patients with musculoskeletal disorders. Through tailored exercise programs and hands-on techniques, physiotherapists work to restore range of motion, strength, and flexibility, enabling patients to perform daily activities with greater ease and efficiency.
3. Faster Recovery from Injuries and Surgeries
For individuals recovering from injuries or surgeries, it plays a crucial role in speeding up the recovery process. By implementing specialized rehabilitation programs, physiotherapists help patients regain strength, coordination, and function, allowing them to return to their normal activities sooner than expected.
4. Prevention of Future Injuries
Orthopaedic physiotherapy not only focuses on treating existing injuries but also on preventing future ones. By educating patients about proper body mechanics, ergonomics, and exercise techniques, physiotherapists empower individuals to reduce the risk of injury and maintain optimal musculoskeletal health in the long run.
Conditions Treated with Orthopedic Physical Therapy
Orthopedic physical therapy caters to a wide array of conditions, including but not limited to:
1. Muscle Strains and Sprains: Common injuries affecting muscles and ligaments.
2. Joint Pain and Arthritis: Conditions causing discomfort and inflammation in joints.
3. Post-Surgical Rehabilitation: Vital for optimizing recovery following orthopedic surgeries.
4. Back and Neck Pain: Addressing issues stemming from spinal problems.
5. Sports Injuries: Rehabilitating athletes back to peak performance safely.
6. Fractures and Dislocations: Assisting in regaining mobility post-injury.
7. Tendonitis and Bursitis: Managing inflammation of tendons and bursae.
8. Osteoporosis: Promoting bone health and minimizing fracture risk.
9. Overuse Injuries: Preventing and treating injuries caused by repetitive motions.
10. Degenerative Conditions: Such as degenerative disc disease or osteoarthritis.
Techniques Used in Orthopaedic Physiotherapy
1. Exercise Therapy
Exercise therapy forms the cornerstone of orthopaedic physiotherapy. Physiotherapists prescribe specific exercises tailored to each patient’s needs and goals. These exercises may include stretching, strengthening, balance training, and functional movements aimed at improving mobility, stability, and muscle function.
2. Manual Therapy
Manual therapy techniques, such as joint mobilization, soft tissue mobilization, and manipulation, are commonly used in it to address musculoskeletal dysfunction. By applying hands-on pressure and manipulation to affected areas, physiotherapists can relieve pain, restore joint mobility, and improve tissue flexibility.
3. Modalities
Modalities such as heat therapy, cold therapy, ultrasound, electrical stimulation, and traction are often utilized in orthopaedic physiotherapy to complement other treatment modalities. These modalities help reduce pain, inflammation, and muscle spasms, facilitating the healing process and enhancing treatment outcomes.
Also Read:
Breaking Down Barriers: How Orthopedic Physiotherapy Is Redefining Rehabilitation
Conclusion
Orthopaedic physiotherapy is a highly effective approach for managing musculoskeletal conditions and injuries. By addressing pain, improving mobility, and enhancing function, physiotherapists play a crucial role in helping patients recover and regain their quality of life. Whether you’re recovering from an injury, managing chronic pain, or seeking to prevent future injuries, it can provide personalized care and support tailored to your individual needs. If you’re experiencing musculoskeletal issues, consider consulting a qualified physiotherapist to explore the benefits of it and start your journey towards better health and wellness.
Ready to explore your options for chiropractic and physiotherapy? Contact SwastyaPhysio today to schedule a consultation and discover the best path to your wellness journey. We’re here to support your health every step of the way.
Banaswadi | HBR layout | Kalyan Nagar | Kammanahalli Horamavu | Hennur
Posted
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-8,518,558,009,144,691,000 | [Skip to Content]
Nemours
Nemours
Providing pediatric care through
the Nemours Children's Health System.
Nemours.org
Hypothyroidism and Hashimoto’s Thyroiditis
What Is the Thyroid?
The thyroid is a small gland below the skin and muscles at the front of the neck, at the spot where a bow tie would rest.
It's brownish red, with left and right halves (called lobes) that look like a butterfly's wings. It weighs less than an ounce, but helps the body do many things, such as get energy from food, grow, and go through sexual development. In younger children, it is also important for brain development.
What Is Hypothyroidism?
Hypothyroidism (or underactive thyroid) is when the thyroid gland doesn't make enough of some important hormones. This makes the body use up energy more slowly, and chemical activity (metabolism) in the cells slows down.
Hypothyroidism is a common condition, especially in adult women. But kids can have it too. Some children are born with it — this is called congenital hypothyroidism. Others develop it later, usually late in childhood or as teens. The most common cause of hypothyroidism in kids and teens is the disease Hashimoto's thyroiditis.
What Are the Signs & Symptoms of Hypothyroidism?
A person with mild hypothyroidism may feel just fine. In fact, it might cause no symptoms at all.
But if thyroid hormone levels get too low, symptoms can become more obvious. These include:
• sluggishness
• depression
• dry skin or hair loss
• feeling cold
• muscle weakness
• poor memory or trouble concentrating
• constipation
• facial puffiness
• weight gain (even when not eating more or exercising less)
• slowed growth
• slow sexual development
• irregular menstrual periods in girls
What Is Hashimoto's Thyroiditis?
Hashimoto's thyroiditis (hah-she-MOE-toes thy-roy-DYE-tiss) is an autoimmune disease. It causes most cases of hypothyroidism in kids and teens. Hashimoto's thyroiditis is also called lymphocytic thyroiditis.
What Happens in Hashimoto's Thyroiditis?
Hashimoto's thyroiditis is an ongoing condition in which the immune system attacks the thyroid. Some people continue to have normal thyroid function. But often, over time the thyroid isn't making enough thyroid hormone, causing hypothyroidism. The body responds by sending a message to the thyroid to work harder to make enough hormone.
This, and the swelling the immune system causes as it attacks the gland, can make the thyroid get bigger, leading to a goiter. The thyroid can keep changing size over months or years.
How Are Hypothyroidism and Hashimoto's Thyroiditis Diagnosed?
To diagnose hypothyroidism and Hashimoto's thyroiditis, doctors ask about a person's symptoms, do an exam, and order blood tests. The tests measure:
• Thyroid hormone levels, particularly thyroxine (T4) and thyroid-stimulating hormone (TSH). T4 is the thyroid hormone made in the thyroid that works throughout the body. TSH is a hormone made in the pituitary gland
(a pea-sized gland just beneath the brain). More TSH is released into the blood when the brain and pituitary sense that the levels of thyroid hormone in the blood are too low. TSH stimulates the thyroid to work harder to make more thyroid hormone.
• Some antibodies (proteins made by the immune system). High levels of these antibodies in the blood are a sign that the gland is being attack by the immune system in Hashimoto's. The two antibodies commonly measured are thyroglobulin antibodies (TgAb) and thyroid peroxidase antibodies (TPO).
How Are Hypothyroidism and Hashimoto's Thyroiditis Treated?
Doctors treat an underactive thyroid with daily thyroid hormone replacement pills. The medicine is the same T4 that the body is no longer making. These will bring the body's levels of thyroid hormone back to normal.
This treatment is fairly simple, but a person will have doctor visits several times a year for an exam, blood tests, and medicine changes as needed.
Reviewed by: Tal Grunwald, MD
Date reviewed: April 2021 | {
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7,994,016,097,429,581,000 | Authors
1. Young, Robert C. MD
Article Content
Being Mortal, the latest in the steady stream of illuminating books on medical subjects by the remarkable surgeon-author Atul Gawande, addresses the problems of aging and end-of -life care. As someone who is solidly on the right side of life's bell-shaped curve, this reviewer found Being Mortal enlightening, instructive, and humanizing.
Figure. No caption a... - Click to enlarge in new windowFigure. No caption available.
Dr. Gawande begins with the perspective of a young medical student. Medical students come to the field because of their compassion and empathy. What they don't have, though, is the knowledge of how to treat and how to cure illness. Their medical education begins a transformation that shifts the physician's focus to that of treatment and away from the more encompassing concept of aid.
ROBERT C. YOUNG, MD.... - Click to enlarge in new windowROBERT C. YOUNG, MD. REVIEWED BY ROBERT C. YOUNG, MD Chairman,
Before concentrating on the central theme of his book, Gawande explores the human desire for independence. In modern societies, this has resulted in a natural evolution toward the separation of families. As he says, "Global economic development has changed opportunities for the young dramatically. Prosperity depends upon escaping the shackles of family expectation to follow their own path." This is true for both children and parents. Parents want "intimacy at a distance." This has led to an entirely new model of how contemporary families live their lives.
He then throws the aging process into this equation, showing how, for many, the gradual and inevitable deterioration of function dramatically alters this dynamic when the adults in the family can no longer be independent. Unlike Gawande's grandfather, who simply aged at home, continuing his role of family patriarch while being cared for by a large and loving family, modern families face a more complex and harder truth: What do we do with Dad?
Gawande then chronicles the development of care centers for aging patients, taking us through the history of poor houses, hospitals, nursing homes, assisted living facilities, and retirement communities. Finally he describes some of the really novel facilities that actually address the elderly's needs for a life with independence and with meaning.
The examples are both instructive and encouraging. But these contemporary care centers face two major obstacles: Regulations, which place legal constraints on them to insure safety, and the constant intervention from medicine's desire to fix. In Gawande's view, "Medical professionals concentrate on repair of health, not sustenance of the soul."
So what do the elderly actually want in the portion of their life that is physically compromised but when death is not imminent? Gawande says: "They ask only to be permitted, insofar as possible, to keep shaping the story of their life in the world-to make choices, and sustain connections to others according to their own priorities."
In the later two chapters-"Letting Go" and "Hard Conversations"-Gawande comes to grips with the central theme: Because being honest about prognosis is so difficult and emotionally charged, and because doctors don't want to dismantle hope, we continually use terms like "regression" and "response," which are technically correct but don't address the fundamental reality of the illness.
This is unrealistic but understandable. But it is also unfair and unprofessional. In a study in British Medical Journal of 500 terminally ill patients, 63 percent of doctors overestimated survival, and only 17 percent underestimated it. Of note, the better the doctor knew the patient, the more likely the estimate was to be incorrect (Christakis and Lamont: BMJ 2000:320:469-473).
One of His Most Effective & Endearing Qualities...
One of Gawande's most effective and endearing qualities is his use of his own shortcomings to illustrate his points. For example, when caring for a patient with thyroid and lung cancer, a partial response to her thyroid cancer led Gawande to suggest that "perhaps experimental therapy could work against both of her cancers"-which he realized was sheer fantasy. He implores us to be honest with patients and with ourselves about the critical distinction between cure and care.
Once that distinction is made and discussed openly, it allows possibilities for a whole new approach to patient care. One can then integrate hospice and/or palliative care with conventional treatments. He quotes what is now a well-known New England Journal of Medicine study on Stage IV lung cancer patients, where half of them received usual care and the other half had usual care plus parallel visits with a palliative care specialist. Those who saw the palliative care specialist entered hospice earlier, stopped chemotherapy earlier, experienced less suffering, and lived 25 percent longer (Temel et al: NEJM 2010;363:733-742).
Gawande devotes substantial portions of the book to conversations between doctors and patients at the end of life. Here, as he says, words matter. You don't ask, "What do you want at the end of your life?" You ask, "If time is short, what is most important to you?" These are difficult but critical questions that enable doctors to deliver what the patient desires and not just what is possible or convenient.
Patients or family members often want the doctor to continue until there is nothing more that can be done. But rarely is there nothing more that doctors can do. We must resist the desire to try to fix something when a different sort of care is required.
Gawande is a master at using his own personal observations and experiences and, as noted, often his own failures to illustrate important lessons. He writes beautifully but succinctly. He seamlessly couples scientific information with personal illustrations. This book should be required reading for anyone entering the field of Oncology. Absorbing his message will make them a better oncologist and a more satisfied doctor.
Gawande leaves us with this thought: "The simple view is that medicine exists to fight death, and that is, of course its most basic task. Death is the enemy. But the enemy has superior forces. Eventually it wins. And in a war you cannot win, you do not want a general who fights to the point of annihilation. You don't want a Custer. You want a Robert E. Lee, someone who knows how to fight for territory that can be won and how to surrender it when it can't."
2014, METROPOLITAN BOOKS, ISBN 0805095152; AVAILABLE IN HARDCOVER, PAPERBACK, KINDLE, AND AUDIO EDITIONS
More OT Book Reviews!
Click to connect to all of Bob Young's OT Book Reviews: bit.ly/OTCollections-Books
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7,188,622,956,981,199,000 | Top
20
Doctor insights on: Should I Came Into Flu Shot If On Methotrexate
Share
Flu Shot (Definition)
Also known as influenza vaccines, flu shots are given out once a year to protect against the flu. The flu shot stimulates the immune system to build antibodies to three or four strains of flu viruses in the hopes that it will offer protection from the current strains present in the community. Each year the Centers for Disease Control (CDC) monitors the strains of Influenza globally and incorporates the appropriate antigens in the new vaccine. For best protection the vaccine ...Read more
3
3
I i took hepatitis b vaccine the first shot subcutaneously , but my friend told me that it should be given intramuscularly ,What should i do now ?
I i took hepatitis b vaccine the first shot subcutaneously , but my friend told me that it should be given intramuscularly ,What should i do now ?
Complete the course: Complete the series over 6 months. Check an antibody titer at the end of the series. You may need another shot in case your antibody titer is not in a protective range. ...Read more
4
4
I gave birth feb 21 2015 and the next day i was given the Depo shot, do3s that take effect immediately into my body or am i still not safe.
I gave birth feb 21 2015 and the next day i was given the Depo shot, do3s that take effect immediately into my body or am i still not safe.
Depo-Provera: When the Depo-Provera injection is given to a woman after she has given birth, or had a miscarriage or an abortion, it works immediately. If given within the first five days of your menstrual cycle, it works 24hrs after the injection. When given after the first five days of your menstrual cycle, it works after 14 days ...Read more
5
5
I got my flu shot jan 5 i now have the flu should I go to the dr its been a month since the shot?
I got my flu shot jan 5 i now have the flu should I go to the dr its been a month since the shot?
Flu shot: Does not for certain take away the chance of flu. By percentage 85% of vaccinated will not, or if they do, it makes the illness less severe. There are specific symptoms of the flu and there is a test for the flu, if in doubt go your doctor for testing and treatment of symptoms at least or if needed, there is a treatment for the flu. ...Read more
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I took the Depo-Provera shot 6 months ago... I've been waiting to get my period so i can get on the pill should I just stick to the shot?
Birth control pills: If you do not want to be on the depo shot, and your cycles are not regular, while the shot completely wears off, consider using a form of birth control pills for a few months. Also, check a pregnancy test. ...Read more
12
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Giving myself Humira (adalimumab) shot, if I did the pull back trick and blood came out, Can I still use the shot? Humira (adalimumab) being too expensive.
Giving myself Humira (adalimumab) shot, if I did the pull back trick and blood came out, Can I still use the shot? Humira (adalimumab) being too expensive.
Yes: The pullback is to avoid injecting the medication directly into a vein. That could kill you. There is no problem at all in repositioning the needle and injecting the med with a little bit of your own blood. Completely safe. ...Read more
13
13
If i been on Depo-Provera 4 years will the shot be in my system 120 days from the day i get my shot?
If i been on Depo-Provera 4 years will the shot be in my system 120 days from the day i get my shot?
Yes, but...: The medication level may not be high enough to prevent pregnancy by then. The medication gradually goes away if another shot is not taken. It will take several months longer to be completely gone from the body. ...Read more
14
14
I been on the Depo-Provera shot for 6 months i recieved two shots and my shot is due now how long will it be before i can get pregnant?
I been on the Depo-Provera shot for 6 months i recieved two shots and my shot is due now how long will it be before i can get pregnant?
Hard to say. : You may be able to get pregnant as early as about 4 months after your last shot. But 6-12 months can be typical. ...Read more
15
15
I got the flu shot last year, but I still got the stomach flu. Why should I bother getting it again this year if it doesn't work?
I got the flu shot last year, but I still got the stomach flu. Why should I bother getting it again this year if it doesn't work?
The flu shot protects against influenza, which isn't the same thing as the stomach flu (gastroenteritis): Gastroenteritis is an infection caused by a variety of viruses, including rotaviruses and noroviruses. Although it is often called the stomach flu, gastroenteritis is not caused by influenza viruses. Influenza attacks your respiratory system — your nose, throat and lungs. Signs and symptoms of influenza may include: Coughing, Congestion, Fever, Muscle aches. Gastroenteritis, on the other hand, attacks your intestines, causing signs and symptoms such as: Diarrhea, Vomiting, Fever, Chills, Headache, Body aches. You can reduce your risk of influenza and gastroenteritis by washing your hands often with soap and water, as well as disinfecting contaminated and frequently touched surfaces. The annual flu vaccine is the most effective way to reduce your risk of getting influenza. Two oral rotavirus vaccines are available for young infants — RotaTeq and Rotarix. ...Read more
18
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I have strep throat, i received a shot of penicillin for it. By Dec 31 it will have been 2 full days since injection. Can i drink on New Years Eve?
I have strep throat, i received a shot of penicillin for it. By Dec 31 it will have been 2 full days since injection. Can i drink on New Years Eve?
Antibiotics alcohol: although alcohol does not reduce the effectiveness of most antibiotics it can delay how quickly you recover from an illness. It's a good idea to recover from your illness before using alcohol. ...Read more
19
19
How much time should I be off my methotrexate before I get the shingles vaccine?
How much time should I be off my methotrexate before I get the shingles vaccine?
2 months: That is somewhat controversial as there is some evidence that it can be given while on methotrexate. The current recommendation is to be off of it for 2 months. ...Read more
Methotrexate (Definition)
Methotrexate was originally used in the early 1950's as a treatment for cancer but was also found to be effective in many other diseases including rheumatoid arthritis and psoriasis. It has anti inflammatory and immunosuppressive properties which make it an excellent first line therapy for RA ...Read more
Dr. Robert Lowe
341 doctors shared insights
Rheumatrex (Definition)
Rheumatrex ...Read more | {
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2,112,242,436,179,307,800 | February 12 - 17, 2025
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Birth control pills, likewise referred to as oral contraceptives, have ended up que es y para que sirve bihecol being a popular and reliable approach of stopping undesirable pregnancies. Nonetheless, numerous women are unclear concerning when to begin taking these tablets and how to utilize them correctly. In this thorough overview, we will supply you with all the details you require to find out about when to start birth control pills.
Understanding Contraceptive Pill
Contraceptive pill contain artificial hormones that work to avoid maternity by reducing ovulation, thinning the cellular lining of the uterus, and enlarging the cervical mucus. These hormones, usually a combination of estrogen and progestin or progestin alone, produce a hormonal setting in the body that makes it difficult for sperm to fertilize an egg or for a fed egg to dental implant in the uterus.
There are different kinds of contraceptive pill readily available, consisting of mix tablets, progestin-only tablets, and extended-cycle pills. Mix pills contain both estrogen and progestin, while progestin-only pills do not include estrogen. Extended-cycle pills are created to reduce the variety of menstrual periods a female has each year.
It is vital to recognize how contraceptive pill work and the different types available to pick the one that finest matches your demands and way of life. Seek advice donde consigo fumarex from your healthcare provider to figure out which sort of contraceptive pill is appropriate for you.
When to Begin Birth Control Pills
The particular timing for starting birth control pills relies on various variables, such as whether you are starting them for the first time, changing from another kind of birth control, or transitioning from postpartum. Right here is a malfunction of when to start contraceptive pill in different circumstances:
• Beginning birth control pills for the first time: If you have never ever used birth control pills in the past, it is advised to start taking them on the very first day of your menstruation. This will certainly offer instant defense versus maternity.
• Switching from an additional kind of contraception: If you are switching from an additional form of birth control, such as condoms or an intrauterine gadget (IUD), it is best to seek advice from your healthcare provider. They will guide you on when and just how to make the transition to birth control pills.
• Transitioning from postpartum: After giving birth, the timing for starting birth control pills can differ. It is generally suggested to wait until six weeks after distribution to begin taking mix birth control pills. However, progestin-only pills can be begun instantly after childbirth.
Always speak with your doctor for personalized guidelines and assistance on when to start birth control pills. They will certainly take into account your medical history, present drugs, and particular needs to supply you with the best suggestions.
Exactly How to Begin Birth Control Pills
Once you have established the suitable time to start birth control pills, follow these actions to guarantee you are using them properly:
• Get a prescription: Contraceptive pill are readily available by prescription only. Arrange an appointment with your doctor to review your options and obtain a prescription.
• Pick up your prescription: Go to a pharmacy to get your contraceptive pill. Ensure you have adequate supply for the whole month.
• Read the instructions: Carefully review the directions provided with your contraceptive pill. Acquaint on your own with the particular dosage, timing, and any kind of extra guidelines.
• Begin on the marked day: Start taking the pills on the assigned day suggested by your healthcare provider. It is critical to take the pills at the very same time each day for optimum performance.
• Adhere to the tablet pack directions: A lot of contraceptive pill been available in a pack with designated days classified. Take one pill each day according to the equivalent day on the pack. If you are not sure, seek advice from the directions or ask your doctor.
• Proceed with routine usage: Once you have begun taking birth control pills, proceed using them continually, also throughout your period. Missing out on pills or taking them inconsistently can lower their effectiveness.
• Think about extra security: While birth control pills are highly effective, they do not secure against sexually transmitted infections (STIs). If you are at risk of acquiring an STI, utilize an obstacle technique of contraception, such as condoms, in addition to birth control pills.
Verdict
Understanding when to begin birth control pills is vital for their effectiveness in avoiding maternity. By recognizing the various kinds of birth control pills, when to begin them based on specific circumstances, and how to use them properly, you can make sure that you are taking the required actions to protect yourself from unwanted pregnancies. Keep in mind to consult with your healthcare provider for personalized advice and recommendations.
Sources
1. American University of Obstetricians and Gynecologists: www.acog.org
2. Planned Parenthood: www.plannedparenthood.org | {
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2,317,673,872,843,083,300 | Engadget
This is Canna-Meds Overseas INC., the actual Exceptional The distribution Pet for Pure-Cannaceutical just by Can-Tek Labs. On the other hand, the often authorized way of thinking is actually the fact that cannabidiol generally routines indirectly within the endocannabinoid receptors CB1 and additionally CB2 just by blocking your malfunction on the compound inside your brain which usually has effects on the data involved with problems, sense and brain features. One additional research, written and published in Found Pharmaceutic Type, observed who CBD could possibly create problems a lot like that regarding certain antipsychotic treatments, which the chemical might make a acquire and also proficient remedy for people who have schizophrenia However, increased scientific studies are vital. Aurora Nordic 1, his or her’s 100,000 sq ft area based out of Odense, Denmark, having a formation capacity for 8,000 kilogram each year connected with healthcare cannabis, most recently attained any making and even drying permit.
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Nowadays I actually try eating 10ml involving David Hanson’s gas that could be a oil such as at the same time THC not to mention CBD. Based to a lot reviews, those who chosen the item veteran fewer soreness although selling some consumer speech. Study tutorials was initially created to maybe you have presume critically in connection with wellbeing upshots of cannabis (we.e., marijuana) has gone south lump, exercising, and even aging. An investigation indicated that any time rodents by means of MS-like warning signs and also problems was completed along with CBD, they decreased IL-1β as well as similar pro-inflammatories (compared to the death that just didn’t attain CBD treatment) (Mecha et al, 2013).
Cannabidiol, or maybe CBD, is often a additive around the cannabis grow crops that won’t have psychoactive benefits the fact that can make any higher. All the hempen necktie current market still has usefulness toward get lawful location to get hemp-derived cannabidiol, and / or CBD the cost of gas, as an ingredient during food products or perhaps nutritional supplements regardless of what the top park expenditures Lead designer Brian Trump ok’d the following 7 days designating hempen necktie as an farm crop. Surely, the invention with the professional medical top features of CBD very much inspired your conception connected with cannabis as a medicine. Within the next scenario, any combined THC and then CBD Air lessened pain in several sclerosis and additionally arthritis.
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-1,444,637,308,251,553,800 | Best Plastic Surgeon in Miami
(305) 861-6881
What Does It Mean to Use an Injectable “Off-Label”?
It is a common practice for doctors to use cosmetic injectable products, such as neurotoxins or dermal fillers, “off-label.” You may have even had a doctor recommend using one of these products off-label to treat your specific anti-aging need or another type of medical condition.
But what does off-label mean, and is it legitimate? Dr. Ary Krau explains more here.
“Off-Label” Uses
Using an injectable product “off-label” means using a drug that is approved for a specific use by the U.S. Food and Drug Administration in another, non-approved way.
The FDA’s goal is to protect and reassure consumers that the drugs and medical devices their doctors use are safe and effective. Companies spend years trying to receive approval of their products from the FDA. They must prove that their product is safe and effective for its intended use and present clinical data to back up these claims. The seal of approval confirms that the benefits of using a product outweigh the potential risks.
Once the FDA approves a product for a specific use, doctors are able to use it for off-label uses as they see fit, based on their experience and knowledge of the product.
Sometimes doctors recommend using approved drugs for non-approved uses to treat a specific condition. Perhaps there may not be an approved drug to treat the specific condition; or, perhaps the doctor has tried all of the approved drugs but they have not produced the desired outcomes.
A great example is Botox Cosmetic, which is currently approved by the FDA to treat forehead lines, crow’s feet lines and glabellar lines (short vertical lines found between the eyebrows). But many doctors recommend using Botox to treat other noticeable signs of aging, such as bands on the neck or downturned corners of the mouth.
Allergan, the manufacturer of Botox, can’t formally advertise these off-label uses, and doctors in private practice may be hesitant to publically promote off-label uses in their marketing materials. However, it is common practice for doctors to suggest those uses during consultation, after they have evaluated you and discussed your specific needs. Also, it’s perfectly appropriate for you to inquire about a doctor’s experience in using a product off-label, and whether they would recommend it for your goals.
Contact Dr. Ary Krau
If you have a question about the approved or off-label use of a specific injectable, feel free to set up a consultation trusted Miami plastic surgeon Ary Krau.
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-4,015,970,002,802,886,000 | Food Addiction
food addictionRecent advances in science have researchers and treatment professionals now believing that food addiction is a legitimate problem that often results in the need for professional help. People who are addicted to food feel significant rewards and pleasure when they eat and these brain reacts in a similar manner as it would if a drug such as heroin or cocaine were used. Highly palatable foods such as sugar, fat or salt are the most common to cause food addiction but an individual could essentially become addicted to just about any flavor or taste.
Much like drug addiction, food addiction is marked by a behavioral or compulsive desire to get a certain substance—in this case it may be sweet snacks, fatty foods or salty flavors. The pleasure experience associated with eating such foods increased dopamine transmission to the brain’s reward pathway causing the addict to feel a burning desire and physical need to eat the food again and again.
For counseling & treatment for food addiction, call 1-800-895-1695
How Food Addiction Develops
Food addiction doesn’t develop overnight. It’s typically a learned behavior that is often the result of having grown up in a household in which certain highly palatable foods were readily available and offered. People who develop an addiction to food will develop a tolerance to the food and may need to eat more and more of the food in order to feel the sense of satisfaction that smaller amounts of the same food once provided.
Most people who are addicted to food will continue to eat despite the known consequences that come from eating. A food addict will eat even though they are overweight, they will eat despite the relationship problems their eating causes and they will continue to eat their food of choice even if it causes problems with their health.
Signs & Symptoms of Food Addiction
There are some common signs & symptoms that signify an addiction to food. Anyone who is overweight or has suffered adverse reactions to their eating habits should consider whether or not they may be showing any of the following signs of food addiction:
• Eating more than was planned
• Eating foods even when not hungry
• Eating until so full that you feel sick
• Worrying about not eating certain foods
• Going out of the way to get certain foods
• Eating despite weight gain or other health problems such as high cholesterol
When to Seek Help
When food addiction is causing problems in your life such as weight gain or failed relationships, it’s time to seek help. If you have tried to stop eating certain foods or have told yourself that you will not eat so much at a single sitting and then overeat or continue to eat the unhealthy food, there could be a legitimate need for professional treatment. Some people will also notice withdrawal symptoms if they don’t have certain foods such as if they don’t have sugar or sweets having a headache or anxiety. Withdrawal from food is another sign that it’s time to seek professional help.
Call our helpline 24/7 for immediate assistance 1-800-895-1695
(Visited 99 times, 1 visits today) | {
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356,259,276,066,637,200 | Question: Can Probiotics Increase Serotonin?
What gut produces serotonin?
In studies done in mice, a team of researchers found that Turicibacter sanguinis, a common gut microbe, can signal nearby intestinal cells to release serotonin, a neurotransmitter typically associated with mammalian mood and digestion (Nat.
Microbiol..
How can I restore my gut flora?
Here are 10 science-based ways to improve your gut bacteria.Eat a Diverse Range of Foods. … Eat Lots of Vegetables, Legumes, Beans and Fruit. … Eat Fermented Foods. … Don’t Eat Too Many Artificial Sweeteners. … Eat Prebiotic Foods. … Breastfeed for at Least Six Months. … Eat Whole Grains. … Eat a Plant-Based Diet.More items…•Nov 18, 2016
How can I increase serotonin and dopamine naturally?
10 Ways to Boost Dopamine and Serotonin NaturallyExercise. Regular exercise for at least 30 minutes each day improves one’s overall mood. … Spend Time in Nature. In previous generations, humans spent most of their time outdoors. … Nutrition. Diet can also influence one’s mental health. … Meditation. … Gratitude. … Essential Oils. … Goal Achievement. … Happy Memories.More items…•Dec 12, 2017
Do antidepressants affect gut?
Studies indicate that the gut microbiota can be significantly affected by antidepressants that target a neurotransmitter called serotonin.
What is the fastest way to increase dopamine?
Here are the top 10 ways to increase dopamine levels naturally.Eat Lots of Protein. Proteins are made up of smaller building blocks called amino acids. … Eat Less Saturated Fat. … Consume Probiotics. … Eat Velvet Beans. … Exercise Often. … Get Enough Sleep. … Listen to Music. … Meditate.More items…•May 10, 2018
Do probiotics increase dopamine?
Summary Probiotics are important not only for digestive health but also for many functions in your body. They’ve been shown to increase dopamine production and improve mood in both animal and human studies.
How can I increase serotonin in my gut?
Eating foods that contain the essential amino acid known as tryptophan can help the body to produce more serotonin. Foods, including salmon, eggs, spinach, and seeds are among those that help boost serotonin naturally.
How do you check serotonin levels?
The serotonin test measures the level of serotonin in the blood. Blood is drawn from a vein (venipuncture), usually from the inside of the elbow or the back of the hand. A needle is inserted into the vein, and the blood is collected in an air-tight vial or a syringe. Preparation may vary depending on the specific test.
What is the happy hormone?
Dopamine. Also known as the “feel-good” hormone, dopamine is a hormone and neurotransmitter that’s an important part of your brain’s reward system. Dopamine is associated with pleasurable sensations, along with learning, memory, motor system function, and more.
What does a lack of serotonin cause?
Low levels of serotonin in the brain may cause depression, anxiety, and sleep trouble. Many doctors will prescribe a selective serotonin reuptake inhibitor (SSRI) to treat depression. They’re the most commonly prescribed type of antidepressant.
Which probiotic is best for anxiety?
How do probiotics help the brain?Probiotic strainWhat science saysB. longummay reduce depression and anxiety, helps people with IBSB. bifidumhelps generate vitamins such as K and B-12, which may also influence moodB. infantisincreased relaxation in rats and helped with treating irritable bowel syndrome4 more rows•Aug 25, 2017
What vitamins help serotonin levels?
Vitamin B6, also known as pyridoxine, has special importance as a precursor of serotonin and tryptophan and can also play a role in behavior and mood. Magnesium is essential for many biochemical reactions in the body and brain.
How does serotonin affect bowel movements?
Those with IBS and high levels of serotonin can have diarrhea, and their rectums are more reactive, with loose or watery stools.
When is the best time to take probiotics?
Probiotics are most effective when they have been taken on an empty stomach to make sure the good bacteria makes it to the gut as quickly as possible. The best time to take a probiotic is either first thing in the morning before eating breakfast or before going to sleep at night.
Do gut bacteria produce serotonin?
Gut bacteria also produce hundreds of neurochemicals that the brain uses to regulate basic physiological processes as well as mental processes such as learning, memory and mood. For example, gut bacteria manufacture about 95 percent of the body’s supply of serotonin, which influences both mood and GI activity. | {
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6,085,961,180,540,581,000 | What is the danger of increasing cholesterol in the blood?
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A bad mood, a headache, and sometimes a lazy person easily writes off during bad weather. Some of these statements are treated with understanding and even with sympathy. Others categorically…
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In the last century, doctors, to protect children from rickets, prescribed fish oil for them and recommended sunbathing. People did not know, and did not try to understand what the…
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Acupuncture
Acupuncture, or acupuncture, is an ancient method of treatment based on the effect of needles on the so-called biologically active points of the body. It is also called reflexotherapy, acupuncture.
Acupuncture originated in ancient China more than 6 thousand years ago. It is based on the teaching of the vital energy of qi, which circulates through the body through special channels – the meridians, thanks to which all human organs and systems work normally. A disease occurs when obstacles appear in the path of energy and its flow is disturbed. As a result, in one organ there is an overabundance of energy, and in the other – its lack, that is, the balance of energies is disturbed. Influencing needles on certain points – biologically active, or reflex ones, it is possible to remove these obstacles and restore the correct passage of Qi along the meridians. How? Each reflex point is associated with a particular organ, and when the needle is mechanically stimulated, the inflow of energy to the diseased organ increases or, on the contrary, weakens.
From the point of view of modern science, stimulation with a needle affects the nerve fibers, as a result of which certain impulses are sent to the brain. They can block a specific part of the brain that is perceiving pain, or it can cause the release of large amounts of endorphins, and thus the effect of pain relief is achieved. In addition, with the help of acupuncture, it is possible to activate a part of the brain that regulates the work of a particular organ, thus improving its innervation and blood supply, which helps to speed up recovery.
Acupuncture in its present form appeared in the early 1930s thanks to the work of Chinese pediatrician Chen Dan’an. He studied various acupuncture practices and summarized their data, instead of using thick needles, he suggested using thin, compiled an exact atlas of points, there are about 700. In our country, acupuncture began to be used from the 1940s, it is recognized by the Ministry of Health and is widely used in medical practice, although Representatives of official medicine still do not have a unanimous opinion about this method: after all, its effectiveness has not been confirmed by clinical trials. Nevertheless, acupuncture has helped rid millions of people of many diseases.
For which diseases acupuncture is used
Acupuncture has a positive effect on a variety of diseases and pathologies. It:
diseases of the musculoskeletal system: arthrosis, arthritis, periarthritis, osteochondrosis, scoliosis, myositis, calcaneal spur, sprain;
respiratory diseases: bronchitis, bronchial asthma, chronic pneumonia (in remission), tracheitis, laryngitis;
diseases of the digestive system: biliary dyskinesia, gastric and duodenal ulcers, gastritis, duodenitis, functional disorders of the gastrointestinal tract;
central and peripheral nervous system diseases: vertebral hernia, radiculitis, neuritis, neuralgia, neurosis, migraine, dizziness, nocturnal enuresis, nervous tic, hysteria;
cardiovascular diseases: hypotension, hypertension, 1–2 nd degree, cardiac block, arrhythmia;
gynecological diseases: menstrual disorders, ovarian dysfunction, sterility caused by hormonal causes, manifestations of menopause;
diseases of the genitourinary system: chronic cystitis, prostatitis, nephritis;
eye diseases: reduced visual acuity, strabismus, oculomotor disorders;
endocrine disorders: thyroiditis, hypothyroidism, mild hyperthyroidism, type 2 diabetes;
allergies: urticaria, neurodermatitis, eczema;
getting rid of bad habits: alcoholism, drug addiction, smoking;
getting rid of excess weight.
How the acupuncture procedure is performed
The doctor feels the area where the needles will be placed to determine the desired point, then treats the skin with alcohol and introduces the needle with a rotational movement. Depending on the desired effect, the needle is inserted at different depths, at different angles and at different times. Sometimes the needles are left for a few days, in these cases they use gold or silver needles. To enhance the therapeutic effect of the needles can supply an electric current.
What are the contraindications
There are a number of contraindications to acupuncture. The absolute ones include mental disorders, tumors, blood diseases, high fever, infectious diseases, complicated pregnancy, up to one year of age, as well as acute pains of unknown origin.
Relative contraindications to acupuncture include impaired cerebral circulation, polio, multiple sclerosis, progressive muscular dystrophy, normal pregnancy, age over 70, and exhaustion and severe physical exhaustion. In these cases, whether the patient can carry out the procedure, the doctor decides.
In addition, it is not recommended to put needles in places with skin lesions, moles and scars, the area of varicose veins. Children under 7 years old do not want to affect the points of the face and front of the head.
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6,396,802,496,421,154,000 | TP53 loss?of?function causes vulnerability to autophagy inhibition in aggressive prostate cancer
Objectives
TP53 loss-of-function is commonly found in aggressive prostate cancer. However, a highly-efficient therapy for this tumor subtype is still lacking. In this study, we investigated the relationship between TP53 mutation status and autophagy in prostate cancer and assessed the efficacy of autophagy inhibitors on TP53-deficient tumors.
Methods
We first evaluated the expression patterns of p53 and autophagy-related proteins, namely LC3B, ULK1 and BECLIN1, as well as their relationship in treatment-naïve and castration-resistant prostate cancer specimens through immunohistochemistry. Subsequently, we generated a Trp53-deleted genetically-engineered mouse model, established prostate tumor organoid lines from the mice and assessed the efficacy of autophagy inhibitors in overcoming Enzalutamide resistance in the tumor organoid model. We also investigated the impact of TP53 re-expression in modulating responses to autophagy inhibitors using LNCaP cell line, which harbored a TP53 missense mutation. Lastly, we attempted to identify potential autophagy-related genes that were crucial for TP53-deficient tumor maintenance.
Results
TP53 loss-of-function was associated with increased levels of autophagy-related proteins in aggressive prostate cancers and Trp53-deleted genetically-engineered mouse-derived tumors. Moreover, the generated androgen receptor-independent tumor organoids were highly vulnerable to autophagy inhibition. Upon TP53 re-expression, not only did the surviving LNCaP cells demonstrate resistance, but they also showed growth advantage in response to autophagy inhibition. Lastly, PEX14, an important peroxisomal regulator was differentially upregulated in aggressive tumors with TP53 loss-of-function mutations, thus implying the importance of peroxisome turnover in this tumor subtype.
Conclusion
Our results support the potential use of autophagy inhibitors in prostate cancers that contain TP53 loss-of-function mutations. | {
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1,045,387,918,947,605,000 | Fact Checked
This Dr. Axe content is medically reviewed or fact checked to ensure factually accurate information.
With strict editorial sourcing guidelines, we only link to academic research institutions, reputable media sites and, when research is available, medically peer-reviewed studies. Note that the numbers in parentheses (1, 2, etc.) are clickable links to these studies.
The information in our articles is NOT intended to replace a one-on-one relationship with a qualified health care professional and is not intended as medical advice.
This article is based on scientific evidence, written by experts and fact checked by our trained editorial staff. Note that the numbers in parentheses (1, 2, etc.) are clickable links to medically peer-reviewed studies.
Our team includes licensed nutritionists and dietitians, certified health education specialists, as well as certified strength and conditioning specialists, personal trainers and corrective exercise specialists. Our team aims to be not only thorough with its research, but also objective and unbiased.
The information in our articles is NOT intended to replace a one-on-one relationship with a qualified health care professional and is not intended as medical advice.
Galangal: The Best Cancer-Fighting Herb Around?
By
Galangal - Dr. Axe
What looks like ginger, acts a little bit like turmeric, but actually has been shown to fight cancer like a champ and can even keep your brain healthy? You (probably haven’t) guessed it: galangal.
This root, part of the ginger family, grows in various parts of Asia and is a staple herb in Thai cooking. The best part about galangal, though, is the way it fights to keep your body healthy. It’s been found to have significant positive effects on eight different types of cancer as well a reduce chronic and specific forms of inflammation, often better than medication.
So, let’s take a journey to explore this herb and exactly how it can benefit your health.
What Is Galangal?
I promise, I’m not trying to fool you — this is not ginger. In fact, galangal is called for in many of the same Asian recipes as ginger because they have significantly unique flavors.
This root spice originated in China and Thailand, making its way into common Ayurvedic medicine. Many people describe its flavor as simultaneously earthy and citrus-like, with a spicy kick. However, galangal isn’t spicy due to capsaicin, like most spicy foods. Instead of leaving you with a lasting burning sensation, it hits you and goes away immediately.
If you’re into Thai food and have tried tom ka gai, a popular Thai soup dish, you may recognize the flavor of galangal root as that peculiar flavor you simply couldn’t place. Well, now that we’ve figured that out, what’s it good for?
The answer to that question may intrigue you, because, in short, it’s good for a lot.
7 Benefits of Galangal
1. Potentially Revolutionary Cancer-Fighting Agent
The most striking health benefit of galangal, according to a massive (and growing) body of scientific research, is its ability to fight and potentially prevent a broad number of cancers and tumors. (1) I’ll review the types of cancer affected by galangal, one by one.
Gastric Cancer
A 2014 study in Iran found that a liquid extract of galangal significantly destroyed the number of gastric cancer cells in a lab test after 48 hours, calling it a “prominent” result. (2)
Leukemia
Acute monocytic leukemia cells, a fast-moving leukemia that begins in the bone marrow, were exposed to a liquid extract of galangal in an effort to find a natural cancer treatment that wouldn’t damage adjoining cells, like dangerous chemotherapy. The researchers in Jamaica conducting the study suggested that this could be a potential cure for this form of leukemia, and that’s not a word scientists use lightly. However, this study was simply the beginning, as much more research must be done to examine the effects of this extract on healthy cells before testing it in living subjects. (3)
Melanoma
Researchers at National Chiayi University in Taiwan studied the impact of three compounds from galangal root on human melanoma (skin cancer) cells. All three compounds had an “antiproliferative” effect, meaning they stopped the growth of new cells. (4)
Pancreatic Cancer
A study released in 2017 tested multiple compounds from galangal in the lab and their impact on pancreatic cancer cells, finding they stopped the growth of new cells and suppressed gene pathways responsible for expanding the cancer’s impact. (5)
Colon Cancer
The first time galangal was studied against human colon cancer cells (in 2013), scientists found it caused apoptosis (cell death) on two types of colon cancer cells. (6)
Breast Cancer
In 2014, an Iranian university found that an extract of galangal spawned apoptosis in the human breast cancer cell line, MCF-7, but did not harm healthy breast cells, MRC-5. (7) Diving more into the method by which galangal achieves this, a medical university study out of China found that it used the TRAIL pathway of cancer treatment to stimulate cell death in breast cancer cells. (8)
Liver (Hepatic) Cancer
One reason cancer is so devastating to the human body has to do with the way it spreads or “metastasizes” to other organs from where it originates. This is especially true with liver cancer. A Taiwan study in 2015 investigating the impact of galangal extracted compounds on HepG2 cells (a type of liver cancer) found that the natural compounds decreased the instance of metastasis by stopping the cells from attaching to other, healthy cells. (9)
In another study related to liver cancer, combination therapy was used with galangal and more common therapy agents, producing an apoptotic effect more significant than the individual therapies displayed. (10)
Cholangiocarcinoma (Bile Duct Cancer)
This particular form of cancer is not as common in the U.S., but it’s an aggressive cancer that infects the bile ducts connecting the liver to the small intestine. It impacts people more commonly in tropical and sub-tropical regions, especially Thailand. The kaempferol rhizome extract from galangal tested in a 2017 Thailand-based study gave the mice subjects longer life spans, less incidence of metastasis and did not produce any noticeable side effects on the subjects. (11)
2. Improves Sperm Count and Function
Certain parts of the galangal root may prove useful in promoting male fertility. In a rat model, researchers in Iran discovered that it increased sperm count and motility (or ability to move). (12)
One study in Denmark looked into the effect a galangal rhizome, paired with a pomegranate fruit extract, had on sperm in healthy human males. Researchers found that the the number of motile sperm increased by three times the amount of the placebo. (13)
3. Acts as an Anti-Inflammatory Agent
Inflammation is at the root of most diseases. This means that chronic inflammation is related to the development of a large number of diseases, including cancer, heart disease, Alzheimer’s disease and several others. Galangal root exhibits an anti-inflammatory effect on the body in a general manner and against specific conditions. (14)
There is a cytokine (cell-signaling protein) found in the human body known as tumor necrosis factor alpha, or TNF-alpha, which regulates immune response. This protein is the subject of a great deal of research because TNF-alpha, if overstimulated, can cause detrimental damage and contribute to fatal diseases with chronic inflammation. A phytonutrient found in galangal suppresses the activity of TNF-alpha and therefore may help reduce inflammation throughout the body. (15)
This herb may also help reduce the inflammation associated with arthritis. In a 2001 study, subjects taking a compound including galangal and ginger extract saw a significant reduction in knee pain and in the need for medications and overall status. (16)
Another condition that may be successfully treated with one of the phytonutrients in this herb (kaempferol) is mastitis. Mastitis is an inflammation of the nipple related to breastfeeding. When treated with kaempferol, the mice in one study found a great reduction in inflammation (related, at least in part, to the suppression of TNF-alpha) to the point that it may be a significant treatment in the future for this condition. (17)
One more particularly significant condition that may benefit from galangal treatment is acute lung injury leading to acute respiratory distress syndrome. This illness is somewhat common, especially among those who are already critically ill, and occurs when fluid leaks into the lungs and stops oxygen from being transferred to vital organs. Unfortunately, acute lung injury is often fatal. (18)
However, galangal’s anti-inflammatory activity seems to have a positive impact on acute lung injury and may be a significant treatment option in the future. (19)
Galangal vs. cancer - Dr. Axe
4. Has Antibacterial and Antifungal Qualities
Galangal extract exerts an antimicrobial effect on several bacteria known for infecting foods, including staphylococcus, E. coli, listeria, salmonella and clostridium. (20) It can even fight amoxicillin-resistant E. coli and actually reverse the resistance some strains have to amoxicillin. (21)
By cooking shellfish with this herb, you may also have a better chance of inhibiting the impact of a bacteria known as vibrio. Vibriosis can affect those who eat undercooked shellfish, particularly oysters, but those effects may be much less likely after adding galangal to your recipe. (22)
Another common bacteria that is, in fact, carried by about 66 percent of the world’s population (according to the Centers for Disease Control and Prevention) is called H. pylori. However, this bacteria may also have met its match when exposed to galangal — in fact, this powerful herb may even help prevent the stomach ulcers commonly caused by the H. pylori bacteria in addition to eliminating the bacteria itself. (23)
5. High in Antioxidants
While we know eating blueberries help us increase our antioxidant intake, you may be interested to know the same is true with galangal — although the types of antioxidants found in it aren’t necessarily the same as those found in fruits you love. Interestingly, the antioxidants in this herb seem most effective in preserving meat products for longer periods of time than without it. (2425)
6. Supports Good Brain Health
Potentially due partly to its anti-inflammatory properties, a compound taken from this root known as ACA could possibly have a brain-protecting effect, decreasing some forms of age-related cognitive degeneration. (26)
Circling back to the TNF-alpha protein, we also find that by regulating TNF-alpha, galangal may even help fight depression. Chronic inflammation and the overreaction of TNF-alpha is a recently studied facet of the discussion surrounding depression. (27)
7. May Ease Stomach Pain and Digestive Issues
While it’s obvious that this root has incredible benefits according to modern science, its oldest and most commonly sought effect is that which it has on an upset stomach. In Ayurvedic medicine and other Asian cultures, it’s used to calm upset stomachs, resolve diarrhea, reduce vomiting and even stop hiccups. (28)
Galangal Nutrition Facts
While galangal and ginger are two different roots, they do come from the same family. “Galangal” refers to any one of four plant species in the Zingiberaceae family: Alpinia galanga (greater galangal), Alpinia officinarum (lesser galangal), Kaempferia galanga (kencur, black galangal or sand ginger) or Boesenbergia rotunda (Chinese ginger or fingerroot). Most scientific research focuses on either the greater or lesser plant species.
Like ginger, this root grows in rhizomes beneath the ground. While it’s not a staple in most Western cooking styles, it’s a common ingredient in Thai and traditional Chinese food.
The rhizomes contain a small amount of calories and other nutrients, although serving sizes vary per recipe and some may include only a minute amount of the spice.
One serving of galangal root (100 grams) contains about: (29)
• 71 calories
• 15 grams carbohydrate
• 1 gram protein
• 1 gram fat
• 2 grams fiber
• 5.4 grams vitamin C (9 percent DV)
Galangal vs. Ginger vs. Turmeric
Often compared to ginger and turmeric, galangal has many similarities to these other two incredibly common dietary condiments.
All three roots have at least some cancer-fighting properties (though galangal’s are the most extensive), reduce inflammation and offer some sort of digestive support. Both turmeric and ginger have been known to help combat diabetes and naturally manage pain, while there is no evidence as of yet that galangal does. Turmeric and galangal, because of their ability to suppress TNF-alpha, both help promote the health of the brain.
Turmeric alone of the three seems to benefit the health of the cardiovascular system. Ginger boasts a weight-loss aspect, and galangal promotes an increased sperm count.
Interestingly, while all three of these have gastrointestinal benefits, galangal may actually increase the amount of stomach acid in some individuals and is not recommended for people with GERD or peptic ulcer disease, whereas the other two can actually be used to treat those conditions.
How to Grow, Use and Cook Galangal
Generally, galangal requires a tropical environment in which to thrive, although it’s possible to grow in more temperate climates when protected from frost. To plant it, place rhizomes about eight inches apart in the early spring. When you’re ready to harvest, gently remove some of the outer rhizomes away from the center, rather than digging up the entire plant (but make sure to give your plant about 12 months to mature before beginning to harvest).
To maintain freshness, leave the skin on until you’re ready to use it. It will keep for several weeks in the refrigerator but can also be frozen or dried to extend shelf life. In cooking, you can use both the fresh herb and the dried rhizomes.
There are a few ways to utilize the root for consumption. One way is to actually chop up the roots and use them in a “decoction,” which simply means to create a “liquor” of sorts from the essence of the rhizome. You can also grind to a powder and create your own homemade supplements, create a tea or just chop or mince it for use in a variety of dishes.
In cooking, feel free to experiment with it. Research shows that many people actually show a taste preference for its pungent yet satisfying flavor, even over other spicy ingredients. (30)
Galangal Recipes
Ready to head over to your local Asian market? Good — you should be, because this stuff is awesome!
No recipe reference for galangal would be complete without a delicious Tom Ka Gai recipe, so let me know what you think of this one.
If you need to satisfy a Thai food craving but don’t have much time, I really enjoy this one-pot Creamy Thai Coconut Chicken Soup.
Galangal History and Interesting Facts
Galangal was cultivated before at least 1000 AD in China. In the late 11th-early 12th centuries, Saint Hildegard of Bingen (a German philosopher and Christian mystic) named galangal “the spice of life,” citing it as one of her very favorite remedies for various ailments. Later, a prominent herbalist is said to have further publicized his use of galangal to treat heart disease, indigestion and even deafness.
Use of this spice spread to Europe, where it was used as everything from a tea for horses to a treatment for nasal infections. In 1898, it was included in the King’s American Dispensatory, a then-current description of the herbs used in American medical practice. Today, Russians use galangal as the base for many of their liquors.
But try this one on for size as the weirdest galangal fact — in 2015, researchers in Malaysia discovered that galangal may actually be an incredibly effective defense against termites. (31) How’s that for spicy?
Precautions
Like most herbs, you should avoid using galangal while pregnant, unless monitored closely by a physician.
Galangal is a relatively hypo-allergenic food, actually suggested in some texts to decrease the intensity of allergic reactions, so the chances are good that you won’t experience any allergy symptoms after consuming it. (32)
As I mentioned before, galangal (specifically Alpinia galanga, or “greater galangal”) may potentially increase the amount of stomach acid you produce. If you have GERD or peptic ulcer disease, it’s probably best to avoid this one unless recommended by your primary care physician. (33)
Final Thoughts
• Galangal, part of the ginger family, is a savory and spicy herb originating from Thailand and China.
• It’s one of the only flavors to add spice without the presence of capsaicin.
• The most widely researched benefit of galangal is its ability to fight cancers.
• Galangal also helps to reduce inflammation, increase sperm count and motility, fight bacterial and fungal infections, support brain health, and ease nausea and other stomach problems.
• “Galangal” refers to any of four types of roots, the two most common being the lesser galangal and greater galangal.
• Turmeric and ginger share some benefits and features with galangal, but all three have distinct flavors and some of their own unique pros.
• It’s challenging but not impossible to grow galangal in less-than-tropic conditions, and you’ll need to wait a minimum of a year before harvesting any of your own to use.
• Galangal is an ancient herb that’s been famous for centuries for its ability to treat various medical conditions.
Read Next: Spikenard Stimulates the Immune System and Relaxes Both Body & Mind
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1,454,450,899,757,946,000 | top of page
WHAT IS BLUE LIGHT?
Sunlight is made up of red, orange, yellow, green, blue, indigo and violet light. When combined, it becomes the white light we see. Each of these has a different energy and wavelength. Rays on the
red end have longer wavelengths and less energy. On the other end, blue rays have shorter wavelengths and more energy. Light that looks white can have a large blue component, which can expose the eye to a higher amount of wavelength from the blue end of the spectrum.
Where are you exposed to blue light?
The largest source of blue light is sunlight. And other sources are
• Fluorescent light
CFL (compact fluorescent light) bulbs
• LED light
Flat screen LED televisions
• Computer monitors, smart phones, and tablet screens
Blue light exposure you receive from screens is small compared to the amount of exposure from the sun. And yet, there is concern over the long-term effects of screen exposure because of the close proximity of the screens and the length of time spent looking at them. According to a NEI-funded study, children’s eyes absorb more blue light than adults from digital device screens.
blue lights benefits for kids
What are the benefits of blue light?
Blue light is needed for good health: • It boosts alertness, helps memory and cognitive function and elevates mood. • It regulates circadian rhythm – the body’s natural wake and sleep cycle. Exposure to blue light during daytime hours helps maintain a healthful circadian rhythm. Too much exposure to blue light late at night (through smart phones, tablets, and computers) can disturb the wake and sleep cycle, leading to problems sleeping and daytime tiredness. • Not enough exposure to sunlight in children could affect the growth and development of the eyes and vision. Early studies show a deficiency in blue light exposure could contribute to the recent increase in myopia/nearsightedness.
computer eye strains and blue lights
How does blue light affect the eyes?
Almost all visible blue light passes through the cornea and lens and reaches the retina. This light may affect vision and could prematurely age the eyes. Early research shows that too much exposure to blue light could lead to: Digital eyestrain: Blue light from computer screens and digital devices can decrease contrast leading to digital eyestrain. Fatigue, dry eyes, bad lighting, or how you sit in front of the computer can cause eyestrain. Symptoms of eyestrain include sore or irritated eyes and difficulty focusing. Retina damage: Studies suggest that continued exposure to blue light over time could lead to damaged retinal cells. This can cause vision problems like age-related macular degeneration.
best protection from blue lights
How to protect eyes from blue light?
What can you do to protect your eyes from blue light? If constant exposure to blue light from smart phones, tablets, and computer screens is an issue, there are a few ways to decrease exposure to blue light: Filters: Screen filters are available for smart phones, tablets, and computer screens. They decrease the amount of blue light given off from these devices that could reach the retina in our eyes. Computer glasses: Computer glasses with yellowtinted lenses that block blue light can help ease computer digital eye strain by increasing contrast. Anti-reflective lenses: Anti-reflective lenses reduce glare and increase contrast and also block blue light from the sun and digital devices.
This message about blue lights and your eyes is brought to you by PreventBlindness.org
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8,005,242,498,058,214,000 | Skip to main content
Loss of function mutation in toll-like receptor-4 does not offer protection against obesity and insulin resistance induced by a diet high in trans fat in mice
Abstract
Background
Toll-like receptor-4 (TLR4) triggers inflammatory signaling in response to microbial lipoploysaccharide. It has been reported that loss of TLR4 protected against saturated fat-induced inflammation and insulin resistance. It is not known whether loss of TLR4 function offers protection against trans fat (TF) induced obesity, inflammation, and insulin resistance. We investigated whether mice with loss of function mutation in TLR4 were resistant to TF-induced pathologies such as obesity, inflammation, hyperglycemia, and hyperinsulinemia.
Methods
C57BL/6j and C57BL/10 mice were cross bred to generate TLR4 mutant and wild type (WT). TLR4 mutant (n = 12) and WT (n = 12) mice were fed either low fat (LF) (13.5% fat energy) or high TF diets (60% fat energy) for 12 weeks. In vitro experiments were conducted on mouse macrophage cells (RAW 264.7 and J774A.1) to investigate whether elaidic (trans 18:1) or oleic acid (cis 18:1) would upregulate inflammatory markers.
Results
TLR4 mutant mice were ~26.4% heavier than WT mice. In both genotypes, mice that received TF diet were significantly heavier than those mice that received LF diet (P < 0.01). TLR4 mutant mice compared to WT mice had significantly higher fasting blood glucose, serum insulin, insulin resistance, serum leptin, and serum cholesterol when they received TF diet (P < 0.05). No upregulation of iNOS or COX2 in response to either elaidic or oleic acid in macrophage cells was observed.
Conclusions
Loss of function mutation in TLR4 not only did not protect mice from TF-induced obesity, hyperglycemia, hyperinsulinemia, and hypercholesterolemia but also exacerbated the above pathologies suggesting that functional TLR4 is necessary in attenuating TF-induced deleterious effects. It is likely that TF induces pathologies through pathways independent of TLR4.
Background
Recently, there has been a considerable interest on the negative health effects of trans fat (TF) in the diet. TFs are unsaturated fats with at least one double bond in the trans configuration. Major dietary sources of TFs are fried foods, bakery products containing hydrogenated vegetable oils and shortenings, margarines, and butter. TFs increase the risk for cardiovascular diseases (CVD) by raising LDL-cholesterol and lipoprotein (a), lowering HDL-cholesterol [1], and adversely affecting the endothelial function [2]. The increased risk of CVD with TF intake is higher than the predicted effects of TF on serum lipids alone suggesting an additional non-lipid role for TF in the pathobiology of CVD [3]. Additionally, epidemiological evidence suggests that increased intake of TF increases the risk of type 2 diabetes [46]. The underlying mechanism through which TF influences the development of type 2 diabetes is not clearly understood.
Toll-like receptors (TLRs) are pattern recognition receptors that play a crucial role in mediating the host's innate immune response against microbial products. TLRs are expressed in various human tissues [7]. The specific TLR, TLR4 has been implicated in fatty acid induced inflammation and insulin resistance [811]. TLR4 is activated by lipopolysaccharide (LPS), a bacterial endotoxin produced by Gram negative bacteria. The binding of LPS with TLR4 is complex and involves CD-14 and the adaptor proteins, MD-2 and myeloid differentiation factor-88 (MyD88). The process recruits interleukin-1 receptor-associated kinase (IRAK) leading to the activation of nuclear factor kappa B (NF-κB) [12, 13]. This activated NF-κB translocates into the nucleus and induces the production of inflammatory cytokines [14].
Recently, several investigators have proposed that saturated fatty acids act as agonists for TLR4. Observations from these studies suggested that the saturated fat-induced TLR4 signaling pathway is a likely mechanism linking dietary fat with inflammation and insulin resistance associated with obesity and type-2 diabetes [9, 10, 1521]. Conversely, loss of function of TLR4 led to the protection of saturated fat-induced insulin resistance and diet-induced obesity in mice [8, 22, 23]. Given the broad spectrum of agonists for TLR4, it is possible that TLR4 may have much broader role than is currently known [18].
Given the similarities between saturated fat and TF in raising blood cholesterol and transducing the production of inflammatory markers, we hypothesized that TF is a potential agonist for the TLR4. Further, we hypothesize that a loss of function mutation in TLR4 may protect against high TF diet-induced inflammation and insulin resistance in mice. Therefore, the objective of this current study was to investigate whether loss of function mutation in TLR4 protects against TF rich diet-induced inflammation and insulin resistance in a mouse model.
Methods
Diets and Reagents
Rodent diet high in TF (Catalog #D06061202) from Research Diets Inc (New Brunswick, NJ) and rodent regular low-fat (LF) chow (control diet) (Catalog #5001) from Lab Diets, Inc were purchased. Nutrient composition of the LF control diet and the high TF diet are presented in Table 1. The high TF diet provided 60% of total dietary energy from fat (34.9 g/100 g) with TF accounting for 65.4% of the total fat content. The source of TF was shortening. The LF diet provided 13.5% energy from fat. The LF diet was trans fat free.
Table 1 Composition of laboratory diets
Oleic and elaidic acids were purchased from Matreya (Pleasant Gap, PA). LPS and bovine serum albumin (BSA) (fatty acid free and low endotoxin) purchased from Sigma (St Louis, MO). Rabbit anti-mouse cyclooxygenase-2 (COX-2) was purchased from Cayman Chemical Co (Ann Arbor, MI). Rabbit anti-mouse inducible nitric oxide synthase (iNOS) was purchased from Upstate (Lake Placid, NY). Donkey anti-rabbit IgG antibodies conjugated with horseradish peroxidase were purchased from GE Health Care (Piscataway, NJ). All other reagents were purchased from Sigma.
Cell culture
Mouse macrophage cell lines RAW 264.7 and J774A.1 cells were cultured in Dulbecco's modified Eagle's medium containing 10% (v/v) heat-inactivated fetal bovine serum albumin (BSA), 100 units/ml penicillin, and 100 μg/ml streptomycin at 37°C in a 5% CO2. Cells (5 × 105) were plated in 6 well plates and cultured in the presence of LPS (20 ng/ml), elaidic acid-BSA, or oleic acid-BSA complexes for 24 h [17]. Supernatants and cell lysates were stored at -80°C until analyzed.
Mice
C57BL6/j and C57BL/10 mice were purchased from Jackson Laboratories (Bar Harbor, ME) and cross bred to generate wild type (WT) mice and mice with loss of function mutation in TLR4. C57BL/6j is the most commonly used background strain for the generation of transgenic mice in research areas such as diabetes, obesity, and immunology because this strain is susceptible to diet-induced obesity and type-2 diabetes. Also, this strain breeds well, has longer life span, and is less susceptible to tumors. C57BL/10 is a homozygous strain for TLR4 mutation. Genotyping was performed on all experimental mice before the study. Genotyping of TLR4 mutant and WT mice were confirmed with PCR. Mice were genotyped using tail DNA extracted with Sigma RedExtract kit from Invitrogen (Carlsbad, CA).
Animals were housed at 22°C with an automatically controlled 12-h light and dark cycles. A total of 24 male mice (12 WT and 12 with the loss of function mutation in TLR4) of 4-wk old were used. Within each genotype, 6 mice received a control LF diet and 6 mice received a high TF diet for 12 weeks. Mice had unlimited access to diets and water. During the course of feeding, food intakes were monitored on a daily basis. All experimental protocols involving animals were approved by the Animal Ethical Committee at Emory University and Georgia State University, Atlanta, GA.
Tissue harvest and liver histology
After collecting blood using the cardiac puncture procedure, liver, cecum, and epididymal fat tissues were separated using sterile equipment and weighed. Liver tissue was placed in 4% paraformaldehyde and embedded in paraffin. Tissue sections of 5 μm in thickness were stained with hematoxylin and eosin and pictures were taken with a microscope that was fitted with a camera.
Measurement of biochemical parameters
At the end of the 12 week feeding period, mice were fasted for 5 h and blood was collected from retrobulbar intraorbital capillary plexus. Serum was generated by centrifugation of blood using serum separator tubes (Becton Dickinson, Franklin Lakes, NJ). Serum was stored after insulin injection at -80°C until analyzed. Serum cholesterol and triglycerides were quantified by colorimetric kits from BioVision (Mountain View, CA). Serum insulin, leptin, and adiponectin were analyzed by ELISA kits purchased from Linco Research Inc (St. Charles, MO). Insulin resistance was calculated from fasting glucose and serum insulin concentrations using homeostatic model assessment (HOMA-IR) (Fasing glucose (mg/dL) × μunits/mL ÷ 450).
Western blotting
COX-2 and iNOS were measured in macrophage cell lysates by immunobloting as previously described (17). IL1-β and IL-6 concentrations in supernatants were measured using ELISA (R&D Systems, Minneapolis, MN) according to the manufacturer's instructions. β-Actin served as a loading control.
Data Analysis
Data were presented as mean ± SD of mean. The effect of genotype (WT and TLR4 mutant) within the diet (LF and TF) was assessed with a 2-way analysis of variance (genotype × diet). Group-wise comparisons between WT and TLR4 mutant mice within the LF or TF diet were performed with Bonferroni posttest (GraphPad Prism software, San Diego, CA). Statistical significance was set at P < 0.05.
Results
Loss of TLR4 did not protect from high TF diet-induced obesity
Average daily food intakes were not significantly different between WT mice and mice with loss of function mutation in TLR4 fed either LF diet (3.2 vs. 3.1 g/d/mouse) or TF diet (2.3 vs. 2.6 g/day/mouse). Visceral fat (fat pad), liver, and cecum morphologies of WT and TLR4 mutant mice are displayed in Figure 1A-C. The appearance of the liver from the TLR4 mutant mice that received TF diets looked paler compared to those mice that received control diet suggesting fat deposition in the liver. Upon further histological examination, TLR4 mutant mice that received TF had more and larger fat vesicles than WT mice that received TF (Figure 2A and 2B).
Figure 1
figure 1
Morphologies of visceral fat (A), liver (B), and cecum (C) of WT and T4Mu mice that received LF and TF diets. Abbreviations: LF, low fat diet (13.5% energy from fat); T4Mu, toll-like receptor-4 loss of function mutant mice; TF, trans fat diet (60% of energy from fat, shortening-based); WT, wild type mice.
Figure 2
figure 2
Liver histology of WT and T4Mu mice that received TF diet. For simplicity, histology related to mice that received LF diet is not presented as there were no differences. Abbreviations: T4Mu, toll-like receptor-4 loss of function mutant mice; WT, wild type mice.
After 12 wk of feeding, body weights were significantly higher in mice with loss of function mutation in TLR4 compared to WT mice that received TF diet (30.2 vs. 38.2 g; P < 0.001). Body weights are presented in Figure 3A. On average, TLR4 mutant mice were ~26.4% heavier in comparison to WT mice. Regardless of genotype, as expected, body weights of mice that received the TF diet were significantly higher compared to body weights of those mice that received LF diet (P < 0.01). Weights of visceral fat pad followed similar patterns (data not shown). Weights of the full-thickness cecum were significantly lower in both genotype mice that received TF diet (P < 0.001) (Figure 3B). Liver and spleen weights were not significantly different between genotypes that received either a LF diet or TF diet or between diet types within the genotype (data not shown).
Figure 3
figure 3
Body weights (A) and cecum weights (B) of WT and T4Mu mice that received LF and TF diets. Significant difference was determined with 2-way analysis of variance (genotype × diet type) for body weights and cecum weights. Body weights and cecum weights are significantly higher in T4Mu mice compared to WT mice that received TF diet. Abbreviations: LF, low fat diet (13.5% energy from fat); T4Mu, toll-like receptor-4 loss of function mutant mice; TF, trans fat diet (60% of energy from fat, shortening-based); WT, wild type mice.
Serum insulin, blood glucose, insulin resistance, serum adipokines, and selected inflammatory markers
Serum insulin and blood glucose concentrations were measured after 5 h fasting. In both genotypes, mice that received TF diet had higher blood glucose and serum insulin concentrations compared to those that received LF diet. Mice with loss of function mutation in TLR4 compared to WT mice had significantly higher blood glucose (116 vs. 83 mg/dL; P < 0.01) and serum insulin concentrations when they received either LF diet or TF diet (Figure 4A and 4B). Insulin resistance, as measured by HOMA-IR was significantly higher in TLR4 mutant mice compared to WT mice when received TF diet (11.2 vs. 1.77; P < 0.001) (Figure 4C).
Figure 4
figure 4
5-hour fasting blood glucose (A), serum insulin (B), and HOMA-IR of WT and T4Mu mice that received LF and TF diets. Significant difference was determined with 2-way analysis of variance (genotype × diet type) for blood glucose, serum insulin, and HOMA-IR. Fasting blood glucose, serum insulin, and HOMA-IR are significantly higher in T4Mu mice compared to WT mice that received TF diet. Abbreviations: HOMA-IR, Homeostatic Model Assessment-Insulin Resistance; LF, low fat diet (13.5% energy from fat); T4Mu, toll-like receptor-4 loss of function mutant mice; TF, trans fat diet (60% of energy from fat, shortening-based); WT, wild type mice.
In vitro studies in the mouse macrophage cell lines RAW 264.7 and J774A1 showed that there was no upregulation of COX-2 and iNOS by TF. In addition, these cells failed to induce and IL-1β and IL-6 in supernatant in response to macrophages treated with either elaidic acid or oleic acid (Figure 5A-C).
Figure 5
figure 5
In vitro experiments on macrophage cell lines (RAW 264.7 and J774A1). No upregulation of inflammatory markers such as IL-1β (A), IL-6 (B), COX2 (C), or iNOS (C) was observed in macrophages in response to treatment with either elaidic acid or oleic acid at 50 μM and 100 μM concentration level. β-actin was used as a loading control. Abbreviations: COX2, cyclooxygenase 2; iNOS, inducible nitric oxide synthase.
We measured serum leptin, adiponectin, serum amyloid A, keratinocyte-derived chemokine, and lipocalin-2 concentrations because these have a role in insulin resistance, type-2 diabetes, and obesity. In both genotypes, serum leptin concentrations were significantly higher in mice that received TF diet compared to those that received LF diet (P < 0.001). The mice with loss of function mutation in TLR4 had significantly higher (~82%) serum leptin concentrations compared to WT mice when they received TF diet (P < 0.002) (Figure 6A). However, there was no significant difference in serum concentrations of adiponectin, serum amyloid A, lipocalin-2, and keratinocyte-derived chemokine between genotypes or diet types (data not shown).
Figure 6
figure 6
5-hour fasting serum leptin (A) and serum cholesterol (B) concentrations of WT and T4Mu mice that received LF and TF diets. Significant difference was determined with 2-way analysis of variance (genotype × diet type) for serum leptin and serum cholesterol. Serum leptin and cholesterol are significantly higher in T4Mu mice compared to WT mice that received TF diet. Serum cholesterol is significantly higher in T4Mu mice compared to WT mice that received LF diet. Abbreviations: LF, low fat diet (13.5% energy from fat); T4Mu, toll-like receptor-4 loss of function mutant mice; TF, trans fat diet (60% of energy from fat, shortening-based); WT, wild type mice.
Serum lipids
Serum total cholesterol concentrations were significantly higher in mice that received TF diet compared to those that received LF diet in both genotypes (P < 0.0001). These serum total cholesterol increases were ~140% and ~78% in WT mice and in mice with loss of function mutation in TLR4, respectively. Mice with loss of function mutation in TLR4 had significantly higher total serum cholesterol compared to WT mice regardless of the diet type they received (P < 0.01). Mice with loss of function mutation in TLR4 had ~140% higher total serum cholesterol when they received LF diet and had ~39% higher total serum cholesterol when they received TF diet (Figure 6B). However, serum trigacylglycerol concentrations were not significantly different between either genotype or diet type (data not shown).
Discussion
Emerging research has established a connection between low grade systemic inflammation and insulin resistance. Insulin resistance is the primary characteristic of obesity and is a risk factor for development of type-2 diabetes. It has been reported that TF intake increased the production of inflammatory markers such as C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and E-selectin [2, 5, 6]. It is likely that TFs are incorporated into plasma membranes of endothelial cells, manocyte/macrophages, and adipocytes which in turn transduces membrane signaling pathways related to inflammation [6]. Although, proinflammatory effect of diets high in TF has been established, the exact molecular mechanism linking TF with inflammatory markers is largely unknown. In this present study, we investigated whether feeding TLR4 mutant mice a diet high in TF would offer protection against TF-induced obesity, insulin resistance, and inflammation in TLR4 mutant mice. We found that loss of function mutation in TLR4 did not protect mice from high TF-diet-induced obesity, hyperglycemia, hyperinsulinemia, hypercholesterolemia, and hyperleptinemia.
What is interesting in this study is that mice with loss of function mutation in TLR4 had gained ~26.4% more weight, had ~39.9% higher blood glucose, had ~57.6% higher serum insulin, had ~78% higher serum cholesterol, and had ~82.5% higher serum leptin compared to their counterpart WT mice when they were fed a diet high in TF. Additionally, TLR4 mutant mice had higher fat deposition than WT mice in the liver when they received TF diet. These observations suggest that functional TLR4 is important in protecting mice from trans fat-induced obesity, hypercholesterolemia, hyperleptinemia, hyperglycemia, and hyperinsulienmia. The exact mechanism through which the loss of function mutation in TLR4 induces the above described pathologies is not known. Recently, our collaborators, Vijay-Kumar et al [24] reported that TLR5 deficient mice also developed obesity, hyperlipidemia, and insulin resistance in response to high fat diet and the transfer of gut microbiota from TLR5 deficient mice to WT-germ-free mice conferred obesity, hyperlipidemia, and insulin resistance (features of metabolic syndrome) to the recipients suggesting that the gut microbiota mediate metabolic derangements associated with high fat diet. Insulin resistance we observed in TLR4 mutant mice in response to TF diet is likely secondary to the increased adiposity of the TLR4 mutant mice. Therefore, it is difficult to accurately assess the effect of TLR4 (or lack of TLR4) on insulin resistance/inflammation in a model where adiposity is not equal.
The possible explanations for the observed results include increased fat absorption in TLR4 mutant mice compared to WT mice or increased energy expenditure in WT mice compared to TLR4 mutant mice may be responsible for the observed pathologies. Also, it is likely that the diet high in TF may have altered the microflora in cecum which in turn may have altered the intestinal barrier allowing translocation of microbial products leading to the activation of TLR4 independent pathways associated with inflammation, dyslipidemia, hyperinsulinemia, insulin resistance, and hyperleptinemia. These pathologies were further exacerbated in the presence of loss of function TLR4 mutation.
To our knowledge, this is the first study that investigated the effects of diet high in TF on obesity and circulating glucose, insulin, leptin, and inflammatory markers in mice with loss of function mutation in TLR4. It has been well established that activation of TLR4 by microbial endotoxin, LPS (TLR4 agonist), triggers the host's innate immune and inflammatory responses leading to the upregulation of pathways relating to insulin resistance and dyslipidemia. One possible mechanism is that LPS stimulates the TLR4 and ERK1/2 signaling which in turn activates hormone sensitive lipase and adipocyte triglyceride lipase. This in turn increases lipolysis in adipocytes leading to free fatty acid (FFA) efflux from adipocytes into the blood [25]. These elevated FFAs interfere with insulin function (unable to suppress hepatic glucose production and stimulate glucose influx into muscle and adipocytes) leading to insulin resistance [2629]. Shi et al [9] reported that FFAs are themselves capable of triggering TLR4 signaling by trasducing production of proinflammatory markers in macrophages, adipocytes, and liver leading to insulin resistance. Insulin resistance is a main pathological abnormality associated with metabolic syndrome, obesity, and type-2 diabetes. Conversely, loss of function mutation in TLR4 protected against diet-induced obesity, hyperinsulinemia and inflammation in response to diet high in saturated fat [23]. Several other investigators proposed that saturated fatty acids act as agonist for TLR4 and therefore linking dietary fat with innate immune system and inflammation [1521, 30, 31]. However, our findings in this model are at odds with the linkage of TLR4 and diet-induced obesity, hyperinsulinemia, and inflammation in response to diet high in saturated fat [23].
Although, we did not observe the blunting of TF diet-induced weight gain, hyperinsulinemina, and hyperglycemia in mice with loss of function mutation in TLR4, our results in this study do not directly contradict the previously proposed connection between saturated fatty acids and upregulation of TRL4 down-stream signaling leading to insulin resistance and inflammation. Well controlled studies by several investigators [23, 32] offered strong evidence that saturated fat diet-induced insulin resistance was blunted in mice that lacked functional TLR4. It is likely that saturated fat and trans fat induce inflammation and insulin resistance by all together different mechanisms.
Conclusions
Our findings suggest that diets high in TF induce obesity, hyperglycemia, insulin resistance, hypercholesterolemia, and hyperleptinemia even in the absence of functional TLR4. Additionally, these pathologies associated with TF diet were exacerbated in the presence of loss of function mutation in TLR4. Furthermore, our results indicate that TLR4 independent pathways may be involved in TF-diet-induced obesity, hyperglycemia, hyperinsulinemia, and hyperleptinemia. Further studies are needed to decipher the complex biomolecular mechanism linking consumption of diets rich in TF with pathologies associated with TLR4 signaling such as insulin resistance, metabolic syndrome, and type-2 diabetes.
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Acknowledgements
This work was supported by the Intramural Grant Program, College of Health and Human Sciences, Georgia State University, Atlanta. Presented in part at the Experimental Biology Annual Meeting, April 2009, New Orleans, LA.
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Correspondence to Vijay Ganji.
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VG, VKM, ATG, and TRG designed research. VKM, JDA, and FAC conducted research. VG analyzed data. VG obtained funding for the study. VG wrote and revised the manuscript. VG, VKM, JDA, FAC, TRZ, and ATG read and approved the final manuscript.
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Vijay-Kumar, M., Aitken, J.D., Carvalho, F.A. et al. Loss of function mutation in toll-like receptor-4 does not offer protection against obesity and insulin resistance induced by a diet high in trans fat in mice. J Inflamm 8, 2 (2011). https://doi.org/10.1186/1476-9255-8-2
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• DOI: https://doi.org/10.1186/1476-9255-8-2
Keywords
• Insulin Resistance
• Wild Type Mouse
• Function Mutation
• Serum Insulin Concentration
• Functional TLR4 | {
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-1,837,350,814,532,440,000 | The secret to better health
It seems that everywhere you turn there’s someone with a revolutionary exercise programme or a ‘magical’ fad-diet that will change your life and improve your health. The truth, however, is that achieving better health is no secret. All it takes is to follow these five simple lifestyle changes and, most importantly, making a commitment to improving your health.
Move more
When it comes to exercise, a little goes a long way for your overall health, and ensuring that you’re moving around during the day is fundamental to keeping your muscles and bones healthy. An easy way to do this is to start walking everywhere and take the stairs where possible. Moving and lifting weighted objects around is also beneficial.
Eat well
The simplest way to eat healthily is to focus on eating ‘real’ foods. Your body needs fruits, vegetables, grains, dairy and some fats to run at its optimum level. Eat a combination of plants and meats, with an emphasis on unprocessed whole foods, which are as close to their natural forms as possible. Avoid processed foods and drinks with sugar, such as soft drinks and juices. Drink plenty of water every day.
Avoid stress
Better health isn’t all about diet and exercise. Your stress levels also play a large role in keeping your body and mind healthy, and in leading a happy life. While stress is a natural part of life, too much of it can raise the cortisol levels in the brain, increasing junk-food cravings which may lead to weight-gain. Stress is also a contributor to depression and can trigger long-term changes in your brain, leading to anxiety disorders and mood swings.
Stress can be managed in a number of ways, from taking deep breaths when you’re feeling overwhelmed, doing calming exercise such as yoga, or seeing a specialist if your stress becomes unmanageable.
Sleep well
Never underestimate the importance of a good night’s sleep. Studies have shown that sleep deprivation can have a negative effect on your health, and it has been linked with many diseases, including obesity and heart disease. The Sleep Health Foundation recommends that adults get between seven and nine quality hours of sleep each night. Ensure that you sleep well by:
• Going to bed and getting up at regular times to tune your body clock.
• Turning off all electronics and dimming the lights 30 minutes before bedtime.
• Avoiding eating a large meal before going to bed.
Read more sleeping tips at The Sleep Health Foundation.
Stick with it
Better health is not a fad-diet or a temporary lifestyle change. It is a conscious decision that you make to commit to a healthy lifestyle, which you can sustain long-term. Better health is a choice you make for yourself and a goal that you work towards for life.
Read more at Authority Nutrition.
Written by ameliath
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Hybridization-Based Detection of Helicobacter pylori at Human Body Temperature Using Advanced Locked Nucleic Acid (LNA) Probes
• Sílvia Fontenete,
Affiliations LEPABE, Laboratory for Process Engineering, Environment, Biotechnology and Energy, Department of Chemical Engineering, Faculty of Engineering, University of Porto, Porto, Portugal, IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal, Nucleic Acid Center, Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark, ICBAS, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal
• Nuno Guimarães,
Affiliations LEPABE, Laboratory for Process Engineering, Environment, Biotechnology and Energy, Department of Chemical Engineering, Faculty of Engineering, University of Porto, Porto, Portugal, IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal, Nucleic Acid Center, Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark
• Marina Leite,
Affiliation IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
• Céu Figueiredo,
Affiliations IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal, FMUP, Faculty of Medicine of the University of Porto, Porto, Portugal
• Jesper Wengel,
Affiliation Nucleic Acid Center, Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark
• Nuno Filipe Azevedo
nazevedo@fe.up.pt
Affiliation LEPABE, Laboratory for Process Engineering, Environment, Biotechnology and Energy, Department of Chemical Engineering, Faculty of Engineering, University of Porto, Porto, Portugal
Hybridization-Based Detection of Helicobacter pylori at Human Body Temperature Using Advanced Locked Nucleic Acid (LNA) Probes
• Sílvia Fontenete,
• Nuno Guimarães,
• Marina Leite,
• Céu Figueiredo,
• Jesper Wengel,
• Nuno Filipe Azevedo
PLOS
x
Abstract
The understanding of the human microbiome and its influence upon human life has long been a subject of study. Hence, methods that allow the direct detection and visualization of microorganisms and microbial consortia (e.g. biofilms) within the human body would be invaluable. In here, we assessed the possibility of developing a variant of fluorescence in situ hybridization (FISH), named fluorescence in vivo hybridization (FIVH), for the detection of Helicobacter pylori. Using oligonucleotide variations comprising locked nucleic acids (LNA) and 2’-O-methyl RNAs (2’OMe) with two types of backbone linkages (phosphate or phosphorothioate), we were able to successfully identify two probes that hybridize at 37 °C with high specificity and sensitivity for H. pylori, both in pure cultures and in gastric biopsies. Furthermore, the use of this type of probes implied that toxic compounds typically used in FISH were either found to be unnecessary or could be replaced by a non-toxic substitute. We show here for the first time that the use of advanced LNA probes in FIVH conditions provides an accurate, simple and fast method for H. pylori detection and location, which could be used in the future for potential in vivo applications either for this microorganism or for others.
Introduction
The human microbiome has long been studied for a better understanding of its influence upon human development, physiology, immunity, and nutrition [1]. In most of these studies, microbial identification methods rely on sample collection followed by DNA isolation and sequencing [2,3]. Despite providing important information on the communities that inhabit the human body, these methods disrupt the spatial structure of the sample, meaning that important information about human/microorganism or microorganism/microorganism interactions might be lost. In addition, the time needed to process a sample is quite long, making these methods less suitable as a diagnostic routine. Hence, novel methods which are able to address those shortcomings, by allowing the direct visualization of microorganisms and microbial consortia (e.g. biofilms) within the human body and in a short period of time, would be invaluable.
Fluorescent in situ hybridization (FISH) using DNA probes has long been used to rapidly detect and localize microbial cells in human clinical samples [4,5]. Nonetheless, this method was never employed to detect microorganisms within the human body (or other higher-order animals). The emergence of a new variant of FISH, here named as fluorescence in vivo hybridization of microorganisms (FIVH), has mainly been hindered by two factors. The first was the lack of suitable systems that were able to detect fluorescence signals within the human body. This issue has been recently overcome, with the arrival of medical devices with built-in advanced imaging systems, such as the confocal endomicroscope that allows an in depth analysis of the mucosa of the stomach [6] or colon [7]. So far, this device has only successfully allowed the detection of microorganisms in the human gastrointestinal-tract using non-specific staining methods [8,9]. The second factor is the lack of control over the FIVH process, as it has to be carried out under the conditions imposed by the microenvironment where the microorganism is to be found. For microorganisms present in the mucosa of the human stomach, for instance, the method would have to be carried out at 37 °C and low pH. Adding to that, DNA probes would have to resist degradation by nucleases [10].
The above-mentioned reasons make it very unlikely for a DNA FIVH method to work, but the evolution of nucleic acid chemistry allowed the development of chemical variations (of the nucleobase, sugar and/or phosphate backbones) of nucleic acids that can replace the DNA as a probe. In fact modified oligonucleotides, such as locked nucleic acids (LNA) or 2’-O-methyl RNA (2’OMe), have been proven to hybridize in vivo with native nucleic acids with low toxic effects [1115], and are hence good candidates to develop a successful FIVH method.
LNA is a nucleic acid analogue with binding sensitivity and specificity towards complementary DNA or RNA targets [16]. LNA contains a ribose ring locked by a O2’-C4’-methylene linkage resulting in a N-type (3-endo) conformation (Figure 1) [17,18]. LNA hybridizes with high affinity toward RNA (and DNA) complementary sequences according to Watson-Crick base-pairing rules, has high resistance to nuclease degradation (high bio-stability), is fully soluble in water, and display low general toxicity in animals [14,16,18]. 2’-O-Methyl-RNA based oligoribonucleotides (2’OMe) (Figure 1) constitute another nucleic acid analogue that is being used as a diagnostic probe in animal cells [1921]. The 2’OMe group induces relatively high affinity towards an RNA target likely due to the C3’-endo conformation adopted by 2’OMe ribose sugars [22]. The use of 2’OMe monomers increases probe’s biostability, improves the specificity and the kinetics of hybridization, and allows targeting under conditions where DNA probes would normally not hybridize [22]. The introduction of LNA monomers into 2’OMe probes increases the target affinity even further due to an additive effect on the melting temperature (Tm) which has been shown to improve the overall detection yield of an experiment [19,23].
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Figure 1. Structures of LNA and 2’ O-methyl RNA monomers (phosphate and phosphorothioate structures) used.
http://dx.doi.org/10.1371/journal.pone.0081230.g001
Other types of modifications may also be incorporated to improve the target’s applicability. For instance, the use of phosphorothioate (PS) oligonucleotides presented some particularly interesting results in the case of human clinical trials as therapeutic agents for the treatment of viral infections and cancer [24,25]. The PS monomers include replacement of one of the two non-bridging oxygen atoms by a sulfur atom at each internucleotide linkage (Figure 1) [26]. These types of oligonucleotides have an increased resistance to exo- and endonucleases when compared to phosphodiester oligonucleotides (PO) [27,28], and are particularly suitable for in vivo applications due to their longer elimination half-life [29].
Taking advantage of recent progress in DNA mimics, the main objective of this work is the development of a FIVH method for the detection of microorganisms at the human body temperature (normothermia) using these novel nucleic acid molecules. As a target microorganism we selected Helicobacter pylori (H. pylori), a gram-negative and microaerophilic bacterium that colonizes the stomach of almost half of the human population and is a major risk factor associated with gastric cancer, the second deadliest cancer worldwide [30,31].
Materials and Methods
Bacterial strains and culture conditions
All bacterial cultures were grown in trypticase soy agar (TSA) supplemented with 5% (vol/vol) sheep blood (Becton Dickinson GmbH, Germany) and incubated for 48 hours at 37 °C under microaerobic conditions. Bacterial density was determined by the dilution of initial culture in water or saline and the absorbance was measured at 600 nm. Initial protocol optimization was performed with H. pylori strain 26695, obtained from the American Type Culture Collection (ATCC 700392, VA USA). For testing the specificity and sensitivity of the probes, other H. pylori strains and Helicobacter spp. were used (Table 1).
Helicobacter spp.
H. pylori strains
26695 (ATCC 700392)
G27 (NCTC 13282)
H. pylori CI-31a
H. pylori CI-116a
Non-pylori Helicobacter strains
H. cinaedi 33221-1.2b
H. mustelae 2H1b
H. salomanisb
H. muridarum 2A5+c
H. pametensisc
H. bilisb
H. canis CIP104753b
Table 1. Helicobacter strains tested in this study.
a - Own isolates
b - Isolate provided by Francis Megraud.
c - Isolate provided by Jay Solnick
CSV
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Oligonucleotide probe design
The 16S rRNA target region was selected based on a previous study [32]. The probe sequences were designed following guidelines for FISH-probes, including limitation of purine content to 60% and restriction of self-complementarity to 3 base pairs. Different types of modified nucleotide monomers were used in the probes (Figure 1). The position and the number of LNA and 2’OMe substitutions used in each probe were based on previous reports [33,34]. At the moment, a specific and reliable thermodynamic model to predict the hybridization temperature is still absent for LNA and 2’OMe-RNA. However is possible to study theoretical melting temperature of each probe through a 2’OMeRNA/Calculator online (http://rnachemlab.ibch.poznan.pl/calculator1.php). As such, we have designed several probes with different sizes to increase the chances of finding one or more probe(s) working at human body conditions (37 °C). Once the probes were selected, a search was conducted at the available 16S rRNA databases of Ribosomal Database Project II (RDP-II), version 10 (http://rdp.cme.msu.edu/) to confirm the theoretical specificity and sensitivity of the probe against other microorganisms. For this analysis, only high quality sequences with more than 1200 bp were selected [35]. It was found that all probes differed by at least two bases (two mismatches) from non-H. pylori species.
Oligonucleotides synthesis and purification
Oligonucleotides were synthesized under anhydrous conditions using standard phosphoramidite chemistry on an automated nucleic acid synthesizer (PerSpective Biosystems Expedite 8909 instrument). LNA and 2’OMe monomers were commercially available from Exiqon and Ribotask, respectively. The syntheses were performed in 1.0 µmol scale using a universal polystyrene-based support. The synthesis conditions used for the incorporation of LNA and 2’OMe monomers were as follows: trichloroacetic acid in CH2Cl2 (3:97) as detritylation reagent; 0.25 M 4,5-dicyanoimidazole (DCI) in CH3CN as activator; acetic anhydride in THF (9:91, v/v) as cap A solution; N-methylimidazole in THF (1:9, v/v) as cap B solution. As an oxidizing solution 0.02 M iodine in H2O/pyridine/THF was used for phosphate oligonucleotides. As a thiolation solution 0.0225 M xanthan hydrate in pyridine/CH3CN (20:90, v/v) was used for phosphorothioate oligonucleotides. Coupling time was 4.6 min for both monomers. Fluorescein phosphoramidite, FAM (Glen Research, VA, USA) was added in anhydrous acetonitrile (0.1 M) and activated by tetrazole with a 20 min coupling time. The stepwise coupling yields (95-99% per step) were based on the absorbance of the dimethoxytrityl cations (DMT+) released after each coupling step. The cleavage from the support was carried out by using 98% aqueous methanol/ammonia solution 7 N in methanol (1:1), 2 h at room temperature followed by 32% aqueous ammonia solution, 12 h at 55 °C.
All oligonucleotides were purified by reversed phase HPLC (RP-HPLC) using a Waters 600 system equipped with an XBridge OST C18 (2.5 µm, 19×100 mm) column and an XBridge Prep C18 (5 µm, 10×10 mm) precolumn. After removal of the DMT-group, oligonucleotides were characterized by ionexchange HPLC (IE-HPLC) on a Dionex system HPLC (VWR) and by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF) on a Microflex Maldi (Bruker instruments, Leipzig, Germany) The purified oligonucleotides were precipitated by acetone and their purity (>90%) and compositions were verified by IE-HPLC and MALDI-TOF analysis, respectively.
Because the probes will target the rRNA of H. pylori, the melting temperature of the synthetic oligonucleotides was assessed using non-modified oligonucleotides consisting only of RNA (HP_RNA_Target), fully complementary to the probes designed here (purchased from Integrated DNA Technologies). A DNA probe to serve as a reference probe (HP_DNA_Ref) with a higher number of bases than the LNA and 2’-OMe probes was purchased from Sigma-Aldrich (MO, USA).
Melting temperature studies
From each strand, 1.0 µM was used in the following buffers: a medium salt buffer with 220 mM Na+ (200 mM NaCl, 20 mM NaH2PO4 and 0.2 mM EDTA, pH 7.0), a medium salt buffer with 30% (vol/vol) formamide and a low salt buffer with 30% (vol/vol) formamide with 110 mM Na+ (110 mM NaCl, 5 mM EDTA, 50 mM Tris-HCl and 30% (v/v) formamide, pH 7.5). After mixing each sample and denaturing the complex by heating up to 85 °C during 5 min, samples were cooled to the starting temperature of the experiment. Quartz optimal cells with a path lengh of 1.0 cm were used. Melting temperatures (Tm values/°C) were measured on Perkin Elmer Lambda 35 UV/VIS spectrometer equipment with a PTP 6 (Peltier Temperature Programmer) and determined as the maximum of the first derivative of the thermal denaturation curve (A260 vs. temperature for medium salt buffer). A temperature range from 13-15°C to 80-85 °C and a ramp of 1.0 °C/min were used. Reported Tm values are an average of two measurements within ± 1°C.
Optimization of probe hybridization conditions on slides and in suspension
The hybridization procedures developed to detect H. pylori were performed by FISH and evaluated by two independent techniques: by fluorescent microscopy on slides (to obtain a faster but qualitative assessment of the fluorescence signal) and by imaging flow cytometry sorting in bacterial suspensions (to obtain a quantitative assessment). Detection of 16S rRNA in slides by FISH was performed mostly as described in Azevedo et al. [36], with a few modifications. For fixation on glass slides, smears of each species/strain were immersed in 4% (v/v) paraformaldehyde for 15 min at room temperature, followed by a treatment of 50% (vol/vol) ethanol for 10 min and allowed to air dry. The hybridization was performed using 20 µl of hybridization buffer with 200 nM of the respective probe, which covered each smear individually. Two different types of hybridization buffer (pH 7.5) were tested: one containing 50% (vol/vol) formamide (Across Organic, New Jersey, US) and the other 4 M of urea (VWR BHD Prolabo, Haasrode, Belgium). The following reagents were common to both buffers: 10% (vol/vol) dextran sulphate (Fisher Scientific, MA, US), 0.1% (vol/vol) Triton-X (Panreac, Barcelona, Spain), 5 mM of EDTA disodium salt 2-hydrate (Panreac), 50 mM Tris-HCl (Fisher Scientificm New Jersey, US), 900 mM NaCl (Panreac). Samples were covered with coverslips and incubated for 90 min at 37 °C. Slides were subsequently washed in a prewarmed solution (pH 10), containing 5 mM Tris Base (Fisher Scientific), 15 mM NaCl (Panreac) and 1% Triton X (Panreac), for 30 min at 37 °C and then, the slides were allowed to air dry. All experiments were performed in triplicate and for each experiment a negative control (same hybridization conditions, but without a probe in the hybridization solution) was included. Slides were stored in the dark before microscopy analysis. For image acquisition a Leica 2000 epifluorescence microscope (Leica Microsystems GmbH, Wetzlar, Germany) was used. FAM-labeling was excited by using a 488 nm laser; the exposure time was fixed for all preparations. The fluorescence intensity of each probe and sample was quantified in the microscopy images using the ImageJ software (http://rsbweb.nih.gov/ij/index.html).
The hybridization method in suspension was based on procedures described by Almeida et al. [37], with slight modifications. Each type of bacterium was collected from one TSA plate with 1 mL of saline and centrifuged at 14 000 x g for 15 min. The pellet was resuspended in 400 µL of 4% (v/v) paraformaldehyde for 1 hour, followed by centrifugation at 14 000 x g for 5 min. The fixed cells were resuspended in 500 µL of 50% (vol/vol) ethanol and incubated at -20°C for at least 30 min. For bacteria disaggregation the samples were subjected to sonication by ultrasounds (Transsonic 420, Elma, Germany) for 12 min, followed by a filtration through a sterile 10 μm pore-size filter (CellTrics®,Görliz, Germany). Afterwards, 100 µL of fixed cells were resuspended in 100 µL of hybridization solution (as previously described) with 400 nM of probe and incubated at 37 °C for 90 min. After hybridization the samples were centrifuged at 14,000 rpm for 5 min, resuspended in 500 µL of washing solution (as described above) and incubated at 37 °C for 30 min. The cells were again centrifuged at 14 000 x g for 5 min and resuspended in 100 µL of saline. To remove aggregates samples were filtered by a sterile filter with 10 μm pore size (CellTrics®). Samples were used directly for imaging flow cytometry analysis.
Image Quantification
Using the ImageJ program (National Institutes of Health Software), each image obtained by microscopy was analyzed for the mean fluorescence intensity. Background values were obtained by measuring a blank region from each image and these were removed from the test frames. Data was plotted as mean of arbitrary fluorescence units (AFU) which represented the mean fluorescence intensity minus background intensities.
Imaging flow cytometry and data analysis
H. pylori bacterial cell suspensions stained with FAM-labeled LNA probes, and the respective unstained negative controls, were analysed in an ImageStream (Amnis Corporation, Seattle WA, USA) imaging flow cytometer equipped with two lasers (488 nm and 785 nm), a 40x magnification objective of 0.75 N.A, and one CDD camera. Images acquired using the INSPIRETM software included a brightfield image (Channel 1, 430-480 nm), and a green fluorescence image (Channel 2, 480-560 nm). During the sample acquisition, the area feature was used as cell classifier, in the brightfield channel, with a lower limit of 2, to exclude debris, and an upper limit of 20, to exclude bacterial aggregates and thus minimize the error in the fluorescence signal intensity that bacterial aggregates would represent in the data analysis. For each sample, 50,000 events were collected and two independent experiments were performed. All imagery data was analysed using the algorithms of IDEAS® v4.0 software (Amnis Corporation). Hierarchical gating schemes were used to further eliminate bacterial aggregates and to determine the spot count and the mean fluorescence signal intensity of each bacterial sample.
Hybridization in gastric biopsies
Formalin-fixed paraffin-embedded biopsies of gastric tissue sections from one patient infected with H. pylori were used. The use of the biopsy for research purposes was previously approved by the ethics committee of the Portuguese Institute of Oncology (IPO) in Porto, and informed written consent was obtained from the patient.Sections were cut to 3 µm thickness, and mounted on microscope glass slides and stored at 4 °C until use. Slides were immersed twice in xylol for 15 min each time, and then subjected to rehydration by decreasing concentrations of ethanol (100%, 95%, 80%, 70% and 50%) for 5 min each time. Finally, slides were washed with distilled water for 10 min and allowed to air dry. Subsequently, the hybridization procedure in slides was used as previously described using both buffers.
Statistical Analysis
Statistical significance was determined by One-way analysis of variance (ANOVA) by applying the Tukey multiple-comparisons test, using SPSS statistics 17.0 (SPSS, Statistical Package for the Social Sciences, Chicago, USA) or Microsoft Office Excel (Microsoft Corporation, Redmond, CA). Differences in data values were considered significant at values lower than 0.05.
Results
Melting temperature behaviour
The initial purpose of this work was to find a type of synthetic oligonucleotide that would be capable of efficiently hybridizing in a bacterium at human body temperature (37 °C). A first screening was performed to determine the melting temperature of 18 synthesized probes (data not shown). The hybridization temperature is not only affected by the type of probe, size and sequence, but also by the amount and type of other substances present in the hybridization solution. For this reason UV thermal denaturation studies were carried out in solutions containing not only the probes, but also different salt concentrations and a denaturing compound (formamide; FA).
After a biophysics analysis comparing melting and hybridization temperatures of the LNA probes (with different lengths), we concluded that the hybridization temperature should be between 15-30 °C lower than the melting temperature measured under similar conditions (i.e. in the presence of salt and FA) (unpublished data). Based on this criterion , four candidate probes, with melting temperatures ranging between 60-70°C were selected for further studies (Table 2).
Medium salt bufferMedium salt buffer with FALow salt buffer with FA
Probes analyzedSequenceRNA complement Tm (°C)RNA complement Tm (°C)RNA complement Tm (°C)
Ref5’-CTGGAGAGACTAAGCCCTCCAA-3’646968
HP_LNA_PO5’-FAM GALCTLAALGCLCCL -3’786967
HP_LNA_PS5’-FAM G*AL*C*TL*A*AL*G*CL*C*CL -3’776866
HP_LNA/2OMe_PO5'- FAM GLACTLAAGLCCCL-3’796667
HP_ LNA/2OMe _PS5'- FAM GL*A*C*TL*A*A*GL*C*C*CL*-3’786366
Table 2. Results of thermal denaturation experiments in different types of buffers for different types of oligoribonucleotides.
The DNA oligonucleotide probe reference (Ref) has the following sequence: 5’-CTGGAGAGACTAAGCCCTCCAA-3’. The RNA complementary oligonucleotide has the following sequence: 5’-UUGGAGGGCUUAGUCUCUCCAG-3’. LNA nucleotide monomers are represented with L superscript, 2’-OMe-RNA monomers in boldface letters, DNA nucleotides in capital letters, and phosphorothioate linkages by the symbol*, FAM- Fluorescein, FA- Formamide.
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Thermodynamically, similar results were observed for the phosphate(HP_LNA_PO and HP_LNA/2OMe_PO) and phosphorothioate (HP_LNA_PS and HP_LNA/2OMe_PS) probes. Phosphorothioate probes (HP_LNA_PS and HP_LNA/2OMe_PS) showed only small differences (only 1°C variation in Tm values) when compared to the respective phosphate probes, with the exception of HP_LNA/2OMe_PS in the medium salt with FA. Although the number of LNA is higher in HP_LNA_PO and HP_LNA_PS probes (5 LNA monomers) than in HP_LNA/2OMe_PO and HP_LNA/2OMe_PS probes (4 LNA monomers) the only significant differences were observed in the melting temperatures when medium buffer with FA was used. It should be noted that the different salt concentration of the salt buffers did not significantly impact the Tm.
FISH detection of H. pylori by fluorescence microscopy
The ability of the selected candidate probes (Table 2) to hybridize at human body temperature (37°C) was then tested using the FISH method in glass slides. In spite of having being designed to work at similar melting temperatures, microscopy results have shown that only the HP_LNA/2OMe_PO and HP_LNA/2OMe_PS probes were able to hybridize at 37 °C (Figure 2A). Because HP_LNA_PO and HP_LNA_PS probes were only able to hybridize at temperatures higher than 40 °C (data not shown), they were not considered for further evaluation. One of the components of the hybridization solution is FA that acts as a denaturing or destabilizing agent allowing the hybridizations to be carried out at lower temperatures. However, it is not possible to use FA in vivo due to its toxic nature to human cells [38]. Therefore, we have tested urea at a 4 M concentration as a suitable non-toxic alternative. The hybridization efficiency of the HP_LNA/2OMe_PS probe was higher than that of the HP_LNA/2OMe_PO probe in both FA and urea buffers, as it can be observed by the high fluorescence signal (Figure 2A). Because fluorescence microscopy only provides qualitative results, we determined the average fluorescence intensity of each sample using ImageJ software (Figure 2B).
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Figure 2. FISH detection of H. pylori 26695 strain (ATCC 700392) using FAM- HP_LNA/2OMe_PO and HP_LNA/2OMe_PS probes.
FISH analysis was performed by epifluorescent microscopy in smears, using either 50% (vol/vol) formamide and 4 M urea as denaturing agents in the hybridization buffer. Smears without probe were used as negative control (Control) (a). (2B) Average fluorescence intensity from each probe in 4 M urea and 50% formamide (v/v) buffers; fluorescent signal intensity is expressed in arbitrary fluorescent units (AFU) and was quantified using the by ImageJ software. All images were acquired at equal exposure conditions. Original magnification: 1000x.
http://dx.doi.org/10.1371/journal.pone.0081230.g002
The results obtained by ImageJ confirmed that the HP_LNA/2OMe_PS probe presents higher fluorescence intensities than the HP_LNA/2OMe_PO probe, irrespectively of the buffer used. The fluorescence intensity of the HP_LNA/2OMe_PS probe is significantly higher in the urea buffer than in the FA buffer (p=0.006). The difference between HP_LNA/2OMe_PS urea and the other analyzed conditions is statistically significant (p<0.05). No statistically significant differences were observed in fluorescence intensity between the HP_LNA/2OMe_PS probe in FA and the HP_LNA/2OMe_PO in both buffer (p>0.05). As expected, control experiments (without probe) showed low levels of fluorescence; this very faint background was likely due to the presence of autofluorescent substances in bacterial cells could be sometimes observed (Figure 2B).
Sensitivity and specificity of the probes are two important factors for the success of a FISH method. Because low hybridization temperatures can influence these two factors, after optimization of the hybridization conditions we have tested the sensitivity and specificity of the candidate probes against the panel of strains presented in Table 1 and in Figure S1. The candidate probes were able to detect H. pylori reference strains and H. pylori clinical isolates, while no fluorescent signal was detected for the non-pylori Helicobacter strains tested. These results showed that 2’-O-methyl/LNA-modified probes were both specific and sensitive for H. pylori strains, even when the hybridization is carried out at 37 °C in the presence of urea as a denaturing agent. A central parameter for a future FIVH application in the human stomach is the optimization of the FISH technique at low pH. As such, preliminary tests using HP_LNA/2OMe_PS analyzed in this study have been performed at pH 4 with positive results (data not shown).
FISH detection of H.pylori by imaging flow cytometry
After optimization of the method on slides, we have applied the FISH procedure to H. pylori suspensions for imaging flow cytometry analysis. The mean fluorescence intensity of each sample was assessed and the overall results were similar to the ones determined by ImageJ for FISH application on slides (Figure 3). The HP_LNA/2OMe_PS probe in urea buffer hybridized with a significantly higher efficiency than that of HP_LNA/2Ome_PS in FA, and HP_LNA/2OMe_PO probe in both buffers (p<0.05), showed by the higher mean fluorescence intensity. Both probes hybridized more efficiently in the 4 M urea buffer than in the FA buffer when compared with the control without probe (Figure 3A and 3B). On the other hand, the both probes in the FA buffer did not show significant differences to the respective control (p>0.05) (Figure 3A and 3B). Under these conditions, using imaging flow cytometry, all different morphological types of H. pylori cells (spiral, coccoid and U-shaped) emitted a bright green fluorescence (Figure 3C).
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Figure 3. FISH detection of H.pylori by imaging flow cytometry.
FAM labeled 2OMe/LNA probes were analysed in 50% (v/v) formamide buffer and in 4M buffer. A) Representative histograms of the green fluorescence intensity of FAM-labeled HP_LNA/2OMe_PO, HP_LNA/2OMe_PS probes and controls. B) Quantification of the mean fluorescence intensity of each probe in two independent experiments obtained by flow cytometry. C) Representative images of individual H. pylori with different morphologies. The population identified as individual H. pylori bacterium by FISH analysis was manually examined and individual cell events were identified. Individual bacterial cells, shown by Brightfield images (BF, left column) and green fluorescence images (SG, right column).
http://dx.doi.org/10.1371/journal.pone.0081230.g003
Gastric biopsy hybridization analysis
Considering the application of 2’-O-methyl/LNA in clinical settings, the identification of H. pylori strains was performed in histological slides of gastric biopsy samples from patients infected with this bacterium. In all paraffin sections, bacterial rRNA was detected using FAM labeled HP_LNA/2OMe_PO and HP_LNA/2OMe_PS probes. However, the analysis of gastric biopsies using HP_LNA/2OMe_PS showed more fluorescence intensity of H. pylori than in the same conditions with HP_LNA/2OMe_PO (data not shown). Negative controls confirmed the lack of autofluorescence from non-labeled H. pylori cells (Figure 4B). Therefore, using hybridization conditions similar to FIVH it is possible to identify and locate the bacteria in the gastric mucosal surface.
thumbnail
Figure 4. FISH detection of H.pylori in paraffin-embedded sections of gastric biopsies, using 2’-O-methyl/LNA FISH detection conditions.
(A) Detection of H. pylori using the HP_LNA/2OMe_PS probe in a histological slide of a gastric biopsy specimen of an infected patient; (B) Experiment control performed in parallel using the HP_LNA/2OMe_PS probe in a histological slide of a gastric biopsy specimen of an non infected patient. Arrows indicate the presence of H. pylori infecting the gastric mucosa. All images were taken at equal exposure times Scale bars: 10 µm. Original magnification of ×1000.
http://dx.doi.org/10.1371/journal.pone.0081230.g004
Discussion
This work presents the first approach to obtain a method for the detection of H. pylori under in vivo mimicking conditions. Taking advantage of the evolution of nucleic acid chemistry, we have synthesized a set of LNA and/or 2’-O-Methyl RNA probes using the standard phosphodiester and the synthetic phosphorothiate backbones and have evaluated their suitability to hybridize at 37 °C.
The hybridization assays showed that only HP_LNA/2OMe_PS and HP_LNA/2OMe_PO probes were able to emit fluorescence at 37 °C. These results suggest that the substitution of DNA for 2’-O-Methyl-RNA nucleotides in LNA probes allows the hybridization to occur at lower temperatures, as long as a shorter LNA/2’-OMe-RNA sequence is used when compared to the corresponding DNA probe. It is furthermore expected that the introduction of 2’OMe monomers into LNA probes will increase probe’s biostability, specificity and kinetics of hybridization, and allows targeting under conditions where DNA/LNA probes do not hybridize, an observation that has been corroborated by others [19,22,23]. We have shown that both HP_LNA/2OMe_PS and HP_LNA/2OMe_PO probes are able to successfully hybridize with H. pylori RNA at 37 °C. The HP_LNA/2OMe_PS probe yield higher fluorescence intensities in slides and in suspensions of H. pylori, as well as in the gastric biopsies, which appears to indicate that phosphorothioate probes are the best candidates to be used as probes in this type of experiments.
Taking in mind the future application of this method to in vivo conditions, and since the FISH procedure includes solutions that are toxic, we have successfully replaced FA by urea. In fact, FA, used as a destabilizing agent of nucleic acid duplexes, is one of the most hazardous chemicals present in the hybridization solution and the use of urea as a substitute has already been suggested by other authors [38]. The replacement of the common 50% (v/v) FA by 4M urea led to a 40% increase in the signal intensity, in both probes analysed (Figure 3), which could be explained by the additional permeabilization role of urea [39]. More importantly, the use of warmed urea-containing buffer did not affect the renaturation kinetics of the reaction.
Although different studies have performed the hybridization step of a FISH process at 37 °C, these typically use a previous denaturation step and a washing step performed at higher temperatures [11,40] or long periods of incubation [41]. Furthermore, some of these studies used DNA probes, and as such the hybridization step alone lasted at least for 8 hours, which is undesirable for the final purpose of FIVH. Furthermore, these experiments have only been performed in animal cells, where nucleic acids are able to diffuse more freely into the cell due to the lack of a cell wall. The present study is the first to perform the detection of a bacterium by FISH at human body temperature used for all steps of the hybridization procedure. The only study that used the designation of FIVH and that was performed in live animal cells [42], applies hybridization in an ex vivo culture environment and as such is not a true FIVH. To the best of our knowledge, the few studies that were performed in vivo in animal cells used fluorescently-labelled small peptides as probes instead of nucleic acids [7]. Another issue observed in this study was the autofluorescence of the tissues in the biopsy. Non-specific fluorescence agents, such as fluorescein, have been used in several studies with endomicroscopy analysis [43]. The sensitivity of this technique allowed for the visualization of small cellular structures such as capillaries and inflammatory cells [44]. Therefore, although autofluorescence is present in the analyzed tissues (Figure 4), published works showed that it is possible to discriminate small fluorescence signals in vivo [45,46]. There are also imaging analysis methods which allow the reduction of autofluorescent signatures from image data mathematically [47,48]. Another possible approach is the use of a different exogenous fluorophores with a different spectral region where tissue autofluorescence cannot be observed [49]. Therefore, if the presence of autofluorescence in fluorescent images becomes a problem in in vivo analysis, there still exist different types of strategies that might allow to overcome this issue.
While significant steps have been taken in here to successfully achieve FIVH in the future, there is still much work to be carried out. For instance, other components employed in the hybridization solutions, such as dextran sulphate and Triton X will have to be substituted or have their concentrations decreased for FIVH application due to their toxicity [50,51]. Dextran sulphate is used as an hybridization rate accelerator [52], whereas Triton X acts as a detergent and prevents non-specific binding. A balance in the concentration of these reagents simultaneously with the concentration of added urea that will ensure reasonable kinetics and specificity of hybridization while keeping acceptable levels of toxicity will have to be accomplished. The exposure time of the probe to the respective target is also one of the most important factors for FIVH success. In fact, the decrease of the time-course of each experiment (30 min) has already been done in our lab for PNA probes (data not shown). Matthiesen and Hansen also tried to reduce the required hybridization time using DNA probes, however, the best results were observed only with one hour of hybridization [53]. Therefore, future studies will be also focused on decreasing the exposure time of the HP_LNA/2OMe_PS probe.
A suitable detection system that is able to detect the fluorescence signal inside the human body to assess the efficiency of hybridization is available to FIVH, using a computer connected to a confocal laser endomicroscope [43]. This equipment has been shown to be useful for in vivo diagnosis of precancerous conditions and gastric cancer, and has also allowed direct, nonspecific in vivo identification of H. pylori [54]. Therefore, it could be used to detect the fluorescence signal of the HP_LNA/2OMe_PS probe in vivo, possibly allowing acquisition of real time high resolution images of this bacterium during ongoing endoscopy. Another important advantage of this method is that it should be easily adapted to detect the resistance of H. pylori to clarithromycin, by a simple redesign of the probes [55]. This would imply that by the end of an endomicroscopy, the gastroenterologist would not only know about the presence of H. pylori, but also have information about the best therapy that should be prescribed to the patient.
In this study, the fluorescence intensity was used as a parameter of probe hybridization efficiency in slides and in suspension. The quantification of fluorescence was performed both by the ImageJ software and by flow cytometry. One of the reasons why the quantification of fluorescence was performed by two methods was that when using flow cytometry it is possible to analyze each cell as an independent observation and therefore stronger statistical data is obtained (Figure 3). The other reason was that, within the human body, not all the microbial cells are adhered to a surface. For instance, when microbial infections of the blood occur, microorganisms such as Candida spp., Staphylococcus aureus and many others can be found in the bloodstream [56,57]. Because one of the goals of this study was to establish a framework for other FIVH methods, we considered it relevant to assess if differences in the hybridization performance could also be observed between hybridization in slides and in suspension. As this was not the case, FIVH might also be applicable in the future as a diagnostic method to detect the causative agent of a septicaemia, pending on the development of suitable technologies to detect the fluorescent signal of the probe.
Conclusions
Specific and sensitive detection by FISH of a microorganism under human normothermia conditions is reported herein for the first time. More importantly, the study also lays the foundation for other projects that aim to develop methods for in vivo detection of other microorganisms using FIVH. For instance, the remarkable properties of LNA in terms of hybridization affinity and specificity were essential for the obtained results. Furthermore, phosphorothioate internucleoside linkages coupled with the introduction of 2’OMe residues proved to be the most suitable probes. As the FIVH process is mostly controlled by the thermodynamics of hybridization of nucleic acids, it is suggested that works targeting other microorganisms should employ LNA/2OMe with PS linkage-based probes.
Future research should be focussed in three main directions: 1) decrease of the time of a standard FISH procedure; 2) evaluation of the cytotoxicity of all compounds used in this process, and 3) assessment of the ability of confocal endomicroscopy to detect the fluorescent signal emitted by the fluorochrome attached to the cells through in vivo studies.
Supporting Information
Figure S1.
Fluorescence intensity results of Helicobacter strains (non 26695 (ATCC 700392)) tested in this study. The results represent the positive signal of each sample after the subtraction of the respective control.
doi:10.1371/journal.pone.0081230.s001
(DOCX)
Acknowledgments
We wish to thank Pedro Madureira of the Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal for the cytometry analysis of preliminary studies and Daniel Carvalho of the Faculty of Engineering (FEUP), University of Porto, Porto, Portugal for the analysis of microscopic images using the ImageJ software. We also thank Mário Dinis-Ribeiro for providing the histological slides of the gastric biopsy specimens.
Author Contributions
Conceived and designed the experiments: SF NG CF JW NFA. Performed the experiments: SF NG ML. Analyzed the data: SF NG JW ML NFA. Contributed reagents/materials/analysis tools: SF NG ML NFA JW CF. Wrote the manuscript: SF NG NFA.
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7,666,783,425,860,596,000 | How Long Will It Take To Shed Those Pounds?
Wondering about the time it takes to lose weight? Well, it’s not the same for everyone. Your starting weight, what you eat, and how active you are play big roles. But don’t worry! Here are some steps and tips to guide you:
The Weight Loss Process
When you start to lose weight, it helps to know how it works. It’s tricky to pin down an exact time for everyone because we’re all unique. Still, health experts say it’s good to aim to lose one to two pounds a week. Why? Because it lasts longer. If you lose weight too fast, you might just get it back. Plus, even a small weight loss can make you healthier by improving your blood sugar levels.
Did you know? People with more weight might lose faster at first because they’re cutting more calories. But it usually slows down later.
What Affects Weight Loss?
Lots of things can change how you lose weight:
Starting weight: If you have more to lose, you might see quick results at first.
What you eat: The kind of food and how many calories you eat make a difference.
Genetics: Your genes can make you lose weight faster or slower.
Does Gender Matter?
Yes! Women usually have more fat than muscle compared to men. This means they burn fewer calories when resting. So, if a guy and a gal eat the same calories, the guy might lose weight faster because of his muscle.
What’s a Calorie Deficit?
It’s a fancy way to say you’re eating fewer calories than your body burns. You can eat less or exercise more to achieve this. If you eat more than you burn, you’ll gain weight. And remember, not everything you eat counts. So, think twice before grabbing that snack!
Don’t Forget To Sleep!
Sleep isn’t just for dreaming. Good sleep helps control hunger and keeps us from wanting junk food. Not getting enough can make us store more fat. And if you’re too tired, you might not feel like moving much, which means burning fewer calories. Aim for 7-9 hours of solid sleep each night.
Why Try Weight Loss Programs?
Everyone’s different. And that’s why custom plans can be great. With expert advice, you get health check-ups and tips on food and lifestyle. Some programs even offer special supplements to help your body’s metabolism. Plus, having a support group can motivate you. It makes the journey fun and keeps you going!
At the end of the day, your body will lose weight in its own way. St. Louis Weight Loss Secret helps you find what works best for you. And remember, it’s more than just about losing weight. It’s about living a healthier, happier life!
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3,246,560,259,131,665,400 | • Reported disease clusters of any kind, including suspected cancer clusters, are investigated by epidemiologists. Epidemiologists use their knowledge of diseases, environmental science, lifestyle factors and biostatistics to try to determine whether a suspected cluster represents a true excess of cancer cases.
• A suspected cancer cluster is more likely to be a true cluster if it involves:
• A large number of cases of one type of cancer, rather than several different types.
• A rare type of cancer, rather than common types.
• An increased number of cases of a certain type of cancer in an age group not usually affected by that type of cancer.
• Epidemiologists try to establish whether the suspected exposure has the potential to cause the reported cancer, based upon what is known about that cancer’s likely cause and what is known about the carcinogenic potential of the exposure. Various statistical methods are used to determine whether the reported excess of cases is really a larger number than normally would be expected to occur.
• For a variety of reasons, most reported cancer clusters are not shown to be true clusters. Many reported clusters do not include enough case for epidemiologists to arrive at any conclusions. Sometimes, even when a suspected cluster has enough cases for study, a true statistical excess cannot be demonstrated. Other times, epidemiologists find a true excess of cases, but they cannot find an explanation for it. For example, the suspected carcinogen may cause cancer only under certain circumstances, making its impact difficult to detect. Moreover, because today’s populations move so often, it can be difficult for epidemiologists to identify previous exposures and find old records.
What is a Cancer Cluster?
A cancer cluster is the occurrence of a greater-than-expected number of cases of a specific cancer within a group of people, a geographic area or a period of time.
Some cancer clusters are random occurrences with unrelated exposes and happen by chance. Some cancer clusters are due to a common exposure and the cause needs to be identified and eliminated. Some factors may indicate that an alleged cluster is due to a common exposure. When evaluating cancer clusters, each cancer site is considered a separate disease.
Some Cancer Facts
• Cancer is the uncontrolled growth and spread of abnormal cells anywhere in the body. Cancer is not just one disease; it is actually an umbrella term for at least 100 different but related diseases.
• Each type of cancer has certain known and/or suspected risk factors associated with it.
• Cancers have many different causes, including smoking, obesity, physical inactivity, genetic predisposition, environmental factors and occupation.
• Environmental factors include not only air, water and soil, but also substances and conditions in the home and workplace. It also includes diet; use of tobacco, alcohol or drugs; and exposure to chemicals, sunlight and other forms of radiation.
• Cancer is almost always caused by a combination of factors that interact in ways that are not yet fully understood.
• Cancer is more likely to occur as people get older; because people are living longer, more cases of cancer can be expected in the future. This may create the impression of an abnormally high number of cancer cases.
• Carcinogenesis (the process by which normal cells are transformed into cancer cells) involves a series of changes within cells that usually occur over the course of many years. More than 10 years can go by between the beginning of carcinogenesis and the diagnosis of cancer, which makes it difficult to pinpoint the cause of the cancer.
• Cancer clusters can occur by chance. For some types and some geographic areas, a small number of cases may be enough to change an area’s cancer rate from below average to above average. While the increase may be real, the additional cases may simply be the result of variations that occur randomly or by chance, and not be due to a single cause. Many communities have below average cancer rates and many others have above average cancer rates. Small communities tend to be more different from average while larger communities tend to be closer to average just because a small community with just a few cases can make a big difference to the rates.
Cancer Cluster Investigations
• Over the past few years, a steadily rising number of suspected clusters of many types of cancer have been reported by the public. The majority of subsequent investigations do not yield a common factor because most cancer clusters occur by chance and are otherwise unrelated.
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-6,674,240,448,725,422,000 | %0 Journal Article %A Emeraud, Cécile %A Yilmaz, Seher %A Fortineau, Nicolas %A Cuzon, Gaëlle %A Dortet, Laurent %T Quality indicators for blood culture: 1 year of monitoring with BacT/Alert Virtuo at a French hospital %D 2021 %J Journal of Medical Microbiology, %V 70 %N 3 %@ 1473-5644 %C 001300 %R https://doi.org/10.1099/jmm.0.001300 %K accreditation %K BacT/AlertVirtuo %K blood culture %K quality indicators %I Microbiology Society, %X Introduction. Blood culture (BC) remains the gold standard for the diagnosis of bloodstream infection. Clinical microbiology laboratories must ensure the quality of their BC process from receipt to definitive results. Aim. In this study, we followed the evolution of different quality indicators for BCs over the first year of implementation of the BacT/Alert Virtuo system in a French hospital. Methodology. In our laboratory, we instituted regular monitoring of several quality indicators to track (i) delays in sample registration, (ii) delays in loading BC bottles in our incubating system (BacT/Alert Virtuo) after registration, (iii) the volume of blood in bottles and (iv) the contamination rates. Results. For 53 892 BC bottles loaded in the BacT/Alert Virtuo from 23 January to 31 December 2019, the delays in sample registration, loading and unloading were respectively 3.5 h±0.016, 44 min±0.209 and 5.8 h±0.0727. Intriguingly, the automated process performed by the BacT/Alert Virtuo system to check the blood volume in bottles was only performed for 60 % of the loaded bottles. Among these, 30 % contained the recommended volume of blood (between 7 and 13 ml). Finally, the contamination rate was found to be 27.2 % for samples at our institution. Conclusions. The delays in sample registration, loading and unloading were found to be acceptable, even though they could be improved by ensuring a continuous service during the night duty period. Furthermore, the percentage of volumes measured is insufficient and must be improved and the majority of bottles do not contain the recommended blood volume. %U https://www.microbiologyresearch.org/content/journal/jmm/10.1099/jmm.0.001300 | {
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5,787,268,504,194,986,000 | Who Is An Ideal Candidate For A Lap Band Procedure?
Today, increasing weight is a problem. Most of the people are suffering from weight problems. Some of obese people do nothing about it and continue to eat whatever they want. But there are some people who are conscious about their fitness and eat healthy food and exercise which is considered the standard for losing weight.
There are some people who have excess weight and need to lose weight as soon as possible to save their lives and that is why need to choose lap band procedure. In order to understand how the lap band surgery works, it is important … Read the rest
Yoga For Weight Loss
It is a myth that yoga does not induce weight loss of any sort. This myth has been fostered by a whole bunch of non believers globally. They feel that yoga is a womans sport or activity. True men are built on a foundation of weight training they feel. This has led to widespread neglect of this fascinating discipline. This is slowly turning into a thing of the past however. Yoga is now attaining steady popularity among all sections of society. Its multifarious benefits can never be ignored. Yoga studios are mushrooming everywhere and instructors are steadily coming into their … Read the rest
Common Treadmill Running Mistakes To Avoid
Cardio equipment running can have its own benefits like protection from unsafe running, heart healthy workouts, etc. But, when you are working out indoors, you should ensure that you make effective use of the workout equipment and protect yourself from any sort of injuries when using them. Generally, most of the first timers commit the following mistakes when running in a treadclimber and getting information about these mistakes can be helpful for you in avoiding them:
It is true that it would be tempting for the first timers to jump into the machine and increase the incline to the desired … Read the rest
Muscle Toning For Weight Loss
Often people enroll themselves into a weight loss regimen only to find that their waistline still measures the same even after indulging in a lot of exercise. This is because most of us are ill-informed about weight loss and how a shrunken waist finally shows.
Weight loss first starts with burning of fat deposited in the layers of skin and muscle. Once this fat is burnt, and your body’s internal systems get regularized, the inch loss begins. This happens only when the so long fat covered muscles get ample exercise and reshape themselves. With even fat distribution in the body … Read the rest | {
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-3,490,628,549,168,310,300 | Microglial production of TNF-alpha is a key element of sustained fear memory
Zhiqian Yu, Hotaka Fukushima, Chiaki Ono, Mai Sakai, Yoshiyuki Kasahara, Yoshie Kikuchi, Nicole Gunawansa, Yuta Takahashi, Hiroo Matsuoka, Satoshi Kida, Hiroaki Tomita
Research output: Contribution to journalArticlepeer-review
41 Citations (Scopus)
Abstract
The proinflammatory cytokine productions in the brain are altered in a process of fear memory formation, indicating a possibility that altered microglial function may contribute to fear memory formation. We aimed to investigate whether and how microglial function contributes to fear memory formation. Expression levels of M1- and M2-type microglial marker molecules in microglia isolated from each conditioned mice group were assessed by real-time PCR and immunohistochemistry. Levels of tumor necrosis factor (TNF)-α, but not of other proinflammatory cytokines produced by M1-type microglia, increased in microglia from mice representing retention of fear memory, and returned to basal levels in microglia from mice representing extinction of fear memory. Administration of inhibitors of TNF-α production facilitated extinction of fear memory. On the other hand, expression levels of M2-type microglia-specific cell adhesion molecules, CD206 and CD209, were decreased in microglia from mice representing retention of fear memory, and returned to basal levels in microglia from mice representing extinction of fear memory. Our findings indicate that microglial TNF-α is a key element of sustained fear memory and suggest that TNF-α inhibitors can be candidate molecules for mitigating posttraumatic reactions caused by persistent fear memory.
Original languageEnglish
Pages (from-to)313-321
Number of pages9
JournalBrain, Behavior, and Immunity
Volume59
DOIs
Publication statusPublished - 2017 Jan 1
Keywords
• Extinction
• Fear memory
• Retention
• TNF-alpha
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-3,507,398,399,677,432,300 | Cardiovascular disease
What is cardiovascular disease?
Cardiovascular disease (CVD) refers to conditions that affect the heart and blood vessels. It is an umbrella term that encompasses diseases such as coronary artery disease, heart attack, heart failure, and stroke.
CVD is the leading cause of death globally. In the US alone, 1 in 4 deaths is attributed to heart disease. Understanding what CVD is and how to prevent it can help promote longevity.
Main Types
The most common types of cardiovascular disease include:
Root Causes
CVD often starts with atherosclerosis - the buildup of plaque inside the arteries. This can be caused by:
Over time, plaque hardens and narrows the arteries, limiting blood flow. If a plaque ruptures, it can cause a heart attack or stroke.
Take control of your heart health today!
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Lifestyle changes and medications (if needed) to treat risk factors can prevent 80% of premature CVD deaths. "An ounce of prevention is worth a pound of cure."
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I hope this overview on what cardiovascular disease entails and how to prevent it was helpful. Let me know if you have any other questions!
Get Free Consultation | {
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3,334,117,302,895,248,400 | Skip to Main Content
Maqui berry
(mok′ē) [Sp. maqui, from Araucanian (Indians of Chile and Argentina)] A South American evergreen shrub (Aristotelia chilensis) that produces black or purple berries. The berries contain natural antioxidants and chemicals that induce quinone reductase.
MAR
medication administration record.
marantic
(mă-ran′tik) [Gr. marantikos] Pert. to marasmus; marasmic.
marasmus
(mă-raz′mŭs) [Gr. marasmos, a wasting away] A generalized wasting and absence of subcutaneous fat caused by malnutrition; emaciation. It results from caloric deficiency secondary to acute diseases, esp. diarrheal diseases of infancy, deficiency in nutritional composition, inadequate food intake, malabsorption, child abuse, failure-to-thrive syndrome, deficiency of vitamin D, or scurvy. SYN: athrepsia; pedatrophy; wasting. SEE: kwashiorkor; protein-energy malnutrition. marasmic (mă-raz′mik), adj.
SYMPTOMS: Signs include loss of muscle mass and other soft tissues and a wizened, sunken face, resembling that of an older person, from loss of temporal and buccal fat pads. Failure to gain weight is followed by a loss of weight. Brain and skeletal growth continues, resulting in a long body and a head too large in proportion to weight. Subcutaneous fat is minimal, the eyes are sunken, and tissue turgor is lost. The skin appears loose and sags. The infant is not active, muscles are flabby and relaxed, and the cry is weak and shrill. The absence of pitting edema of the hands and feet and of a protuberant abdomen differentiate this condition from kwashiorkor, but in marasmic kwashiorkor, features of both conditions are combined.
TREATMENT: Initial feedings should be small and low in calories because digestive capacity is poor and a "refeeding" syndrome can occur, marked by hypophosphatemia, congestive heart failure, respiratory distress, convulsions, coma, and death. Diluted formula or breast milk is best. The amount of calories and protein, carbohydrates, and fat should be increased gradually. The goal for protein intake is 5 g/kg of body weight per day. If diarrhea due to disaccharidase deficiency is present, a low-lactose diet is beneficial. Parenteral fluid therapy is indicated if shock or fluid and electrolyte imbalance exists.
PROGNOSIS: Death occurs in 40% of affected children.
marble bone disease
Osteopetrosis.
Marburg virus disease
(mar′būrg) [Marburg, Germany where laboratory workers caught the disease from infected African green monkeys in 1967] A frequently fatal disease caused by a virus classed as a member of the family Filoviridae. Clinically this disease is identical to that caused by the Ebola virus. SEE: Ebola virus hemorrhagic fever.
marc
(mărk) [Fr.] The residue remaining after a drug has been percolated. SEE: percolation.
Marcus Gunn dots, pupil, syndrome
SEE: under Gunn, Robert Marcus.
maresin
[fr. ...
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-5,165,778,815,161,843,000 | قالب وردپرس درنا توس
Home / Health / Would you like to reduce the risk of skin cancer? Follow the rules of the sunscreen application.
Would you like to reduce the risk of skin cancer? Follow the rules of the sunscreen application.
Get the Know Your Value Newsletter
Protecting your skin from the sun requires some effort, but it's worth reducing the risk of skin cancer and aging. However, protecting yourself is much more than just a few sunscreens, if you remember. Science shows regular use of the right sunscreen is the key to reducing the health risks associated with the sun. There are a few simple rules when it comes to sunscreen.
̵
1; Look for a broad-spectrum product that blocks both UVA and UVB rays from the sun.
– Select at least one SPF (sun protection factor)
– Use a "shot-glass" size for your face and body (about 2 ounces).
– Remember to apply to your lips – they burn easily.
-If use a spray sunscreen, rub it in the skin after applying.
Apply 30 minutes before sun exposure.
– Apply after swimming or every two hours when you are outdoors.
-Wear sunscreen every day on cloudy days
Who needs sunscreen? Everyone! Regardless of age, race or gender, every fifth American develops skin cancer during his lifetime. Daily use of a high (15+) SPF sunscreen every day can help reduce this risk. Remember that sand, water and snow all reflect the rays of the sun, so wear sunscreen every day.
Madelyn Fernstrom, PhD, is NBC's News Health Editor. Follow her on Twitter @drfernstrom.
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